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Isaacs A, Zeemering S, Winters J, Batlle M, Bidar E, Boukens B, Casadei B, Chua W, Crijns HJGM, Fabritz L, Guasch E, Hatem SN, Hermans B, Kääb S, Kawczynski M, Maesen B, Maessen J, Mont L, Sinner MF, Wakili R, Verheule S, Kirchhof P, Schotten U, Stoll M. Lateral Atrial Expression Patterns Provide Insights into Local Transcription Disequilibrium Contributing to Disease Susceptibility. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2025; 18:e004594. [PMID: 39846178 DOI: 10.1161/circgen.124.004594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 11/19/2024] [Indexed: 01/24/2025]
Abstract
BACKGROUND Transcriptional dysregulation, possibly affected by genetic variation, contributes to disease etiology. Due to dissimilarities in development, function, and remodeling during disease progression, transcriptional differences between the left atrium (LA) and right atrium (RA) may provide insight into diseases such as atrial fibrillation. METHODS Lateral differences in atrial transcription were evaluated in CATCH ME (Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly) using a 2-stage discovery and replication design. The design took advantage of the availability of 32 paired samples, for which both LA and RA tissue were obtained, as a discovery cohort, and 98 LA and 69 RA unpaired samples utilized as a replication cohort. RESULTS A total of 714 transcripts were identified and replicated as differentially expressed (DE) between LA and RA, as well as 98 exons in 55 genes. Approximately 50% of DE transcripts were colocated with another frequently correlated DE transcript (PFDR ≤0.05 for 579 regions). These "transcription disequilibrium" blocks contained examples including side-specific differential exon usage, such as the PITX2 locus, where ENPEP showed evidence of differential exon usage. Analysis of this region in conjunction with BMP10 identified rs9790621 as associated with ENPEP transcription in LA, while rs7687878 was associated with BMP10 expression in RA. In RA, BMP10 and ENPEP were strongly correlated in noncarriers, which was attenuated in risk-allele carriers, where BMP10 and PITX2 expression were strongly correlated. CONCLUSIONS These results significantly expand knowledge of the intricate, tissue-specific transcriptional landscape in human atria, including DE transcripts and side-specific isoform expression. Furthermore, they suggest the existence of blocks of transcription disequilibrium influenced by genetics.
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Affiliation(s)
- Aaron Isaacs
- CARIM School for Cardiovascular Diseases (A.I., S.Z., J.W., B.B., H.J.G.M.C., B.H., M.K., S.V., U.S., M.S.), Maastricht University, the Netherlands
- Maastricht Center for Systems Biology (A.I.), Maastricht University, the Netherlands
- Department of Physiology (A.I., S.Z., J.W., B.B., B.H., M.K., S.V., U.S.), Maastricht University, the Netherlands
| | - Stef Zeemering
- CARIM School for Cardiovascular Diseases (A.I., S.Z., J.W., B.B., H.J.G.M.C., B.H., M.K., S.V., U.S., M.S.), Maastricht University, the Netherlands
- Department of Physiology (A.I., S.Z., J.W., B.B., B.H., M.K., S.V., U.S.), Maastricht University, the Netherlands
| | - Joris Winters
- CARIM School for Cardiovascular Diseases (A.I., S.Z., J.W., B.B., H.J.G.M.C., B.H., M.K., S.V., U.S., M.S.), Maastricht University, the Netherlands
- Department of Physiology (A.I., S.Z., J.W., B.B., B.H., M.K., S.V., U.S.), Maastricht University, the Netherlands
| | - Montserrat Batlle
- Institute of Biomedical Research August Pi Sunyer, Barcelona, Spain (M.B., E.G., L.M.)
- CIBERCV, Madrid, Spain (M.B., E.G., L.M.)
| | - Elham Bidar
- Departments of Cardiothoracic Surgery (E.B., M.K., B.M., J.M.), Maastricht University Medical Centre, the Netherlands
| | - Bas Boukens
- CARIM School for Cardiovascular Diseases (A.I., S.Z., J.W., B.B., H.J.G.M.C., B.H., M.K., S.V., U.S., M.S.), Maastricht University, the Netherlands
- Department of Physiology (A.I., S.Z., J.W., B.B., B.H., M.K., S.V., U.S.), Maastricht University, the Netherlands
| | - Barbara Casadei
- NIHR Oxford Biomedical Research Center, John Radcliffe Hospital, University of Oxford, United Kingdom (B.C.)
| | - Winnie Chua
- Institute of Cardiovascular Sciences, Birmingham, United Kingdom (W.C., L.F., P.K.)
| | - Harry J G M Crijns
- CARIM School for Cardiovascular Diseases (A.I., S.Z., J.W., B.B., H.J.G.M.C., B.H., M.K., S.V., U.S., M.S.), Maastricht University, the Netherlands
- Cardiology (H.J.G.M.C.), Maastricht University Medical Centre, the Netherlands
| | - Larissa Fabritz
- Institute of Cardiovascular Sciences, Birmingham, United Kingdom (W.C., L.F., P.K.)
- University Center of Cardiovascular Sciences, University Medical Center Hamburg Eppendorf, Germany (L.F.)
- German Center for Cardiovascular Research (DZHK), Hamburg/Kiel/Lübeck, Germany (L.F., S.K., M.F.S., P.K.)
| | - Eduard Guasch
- Institute of Biomedical Research August Pi Sunyer, Barcelona, Spain (M.B., E.G., L.M.)
- CIBERCV, Madrid, Spain (M.B., E.G., L.M.)
- Clinic Barcelona, Universitat de Barcelona, Spain (E.G., L.M.)
| | - Stephane N Hatem
- INSERM UMRS 1166, Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne University, Paris, France (S.N.H.)
| | - Ben Hermans
- CARIM School for Cardiovascular Diseases (A.I., S.Z., J.W., B.B., H.J.G.M.C., B.H., M.K., S.V., U.S., M.S.), Maastricht University, the Netherlands
- Department of Physiology (A.I., S.Z., J.W., B.B., B.H., M.K., S.V., U.S.), Maastricht University, the Netherlands
| | - Stefan Kääb
- German Center for Cardiovascular Research (DZHK), Hamburg/Kiel/Lübeck, Germany (L.F., S.K., M.F.S., P.K.)
- University Heart and Vascular Center, University Hospital Hamburg Eppendorf, Germany (S.K., M.F.S.)
- Department of Cardiology, University Hospital of Munich, Germany (S.K., M.F.S.)
| | - Michal Kawczynski
- CARIM School for Cardiovascular Diseases (A.I., S.Z., J.W., B.B., H.J.G.M.C., B.H., M.K., S.V., U.S., M.S.), Maastricht University, the Netherlands
- Department of Physiology (A.I., S.Z., J.W., B.B., B.H., M.K., S.V., U.S.), Maastricht University, the Netherlands
- Departments of Cardiothoracic Surgery (E.B., M.K., B.M., J.M.), Maastricht University Medical Centre, the Netherlands
| | - Bart Maesen
- Departments of Cardiothoracic Surgery (E.B., M.K., B.M., J.M.), Maastricht University Medical Centre, the Netherlands
| | - Jos Maessen
- Departments of Cardiothoracic Surgery (E.B., M.K., B.M., J.M.), Maastricht University Medical Centre, the Netherlands
| | - Lluis Mont
- Institute of Biomedical Research August Pi Sunyer, Barcelona, Spain (M.B., E.G., L.M.)
- CIBERCV, Madrid, Spain (M.B., E.G., L.M.)
- Clinic Barcelona, Universitat de Barcelona, Spain (E.G., L.M.)
| | - Moritz F Sinner
- German Center for Cardiovascular Research (DZHK), Hamburg/Kiel/Lübeck, Germany (L.F., S.K., M.F.S., P.K.)
- University Heart and Vascular Center, University Hospital Hamburg Eppendorf, Germany (S.K., M.F.S.)
- Department of Cardiology, University Hospital of Munich, Germany (S.K., M.F.S.)
| | - Reza Wakili
- Department of Medicine and Cardiology, Goethe University, Frankfurt, Germany (R.W.)
- German Center for Cardiovascular Research DZHK, Rhine-Main (R.W.)
| | - Sander Verheule
- CARIM School for Cardiovascular Diseases (A.I., S.Z., J.W., B.B., H.J.G.M.C., B.H., M.K., S.V., U.S., M.S.), Maastricht University, the Netherlands
- Department of Physiology (A.I., S.Z., J.W., B.B., B.H., M.K., S.V., U.S.), Maastricht University, the Netherlands
| | - Paulus Kirchhof
- Institute of Cardiovascular Sciences, Birmingham, United Kingdom (W.C., L.F., P.K.)
- Department of Cardiology, University Heart and Vascular Center Hamburg, Germany (P.K.)
- German Center for Cardiovascular Research (DZHK), Hamburg/Kiel/Lübeck, Germany (L.F., S.K., M.F.S., P.K.)
| | - Ulrich Schotten
- CARIM School for Cardiovascular Diseases (A.I., S.Z., J.W., B.B., H.J.G.M.C., B.H., M.K., S.V., U.S., M.S.), Maastricht University, the Netherlands
- Department of Physiology (A.I., S.Z., J.W., B.B., B.H., M.K., S.V., U.S.), Maastricht University, the Netherlands
| | - Monika Stoll
- CARIM School for Cardiovascular Diseases (A.I., S.Z., J.W., B.B., H.J.G.M.C., B.H., M.K., S.V., U.S., M.S.), Maastricht University, the Netherlands
- Department of Biochemistry (M.S.), Maastricht University, the Netherlands
- Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Germany (M.S.)
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Yan Z, Pu X, Chang X, Liu Z, Liu R. Genetic basis and causal relationship between atrial fibrillation and sinus node dysfunction: Evidence from comprehensive genetic analysis. Int J Cardiol 2025; 418:132609. [PMID: 39389108 DOI: 10.1016/j.ijcard.2024.132609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/16/2024] [Accepted: 09/30/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND Atrial fibrillation (AF) and sinus node dysfunction (SND) are commonly observed together clinically. However, little is known about the genetic background and causal relationship between the two. METHODS Firstly, we investigated the global and local genetic correlations between AF and SND using LDSC and HESS. Then, we identified shared "Novel SNPs" between AF and SND through two complementary cross-trait meta-analyses and mapped the "pleiotropic genes" behind these SNPs, validated by colocalization analysis. Additionally, we explored the degree of genetic enrichment of SNPs in specific tissues using LDSC-SEG and MAGMA, and identified potential functional genes in tissues using summary data-based Mendelian randomization (SMR). Finally, two-sample Mendelian randomization (TSMR) and multivariable Mendelian randomization (MVMR) were used to explore the causal relationship between AF and SND. RESULTS Both global and local genetic correlation analyses revealed a high positive genetic correlation between AF and SND. HESS identified 9 shared loci, with chr4(q25-q26) and chr11(p11.12-q11) being prominent. Cross-trait meta-analysis and colocalization analysis identified ENPEP and PITX2 as novel pleiotropic genes. MAGMA revealed genetic enrichment of SNPs for AF and SND in the "Heart Left Ventricle" and "Heart Atrial Appendage" tissues, with CEP68 and BEST3 identified as potential functional genes through SMR. MR analysis indicated that AF increases the risk of SND, even after adjusting for confounding factors. CONCLUSION This study provides genetic evidence for the increased risk of SND associated with AF, identifying multiple shared risk loci and enriched tissues, and discovering 2 novel pleiotropic genes and 2 new functional genes.
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Affiliation(s)
- Zhaoqi Yan
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiangyi Pu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Heriot-Watt University, Edinburgh, United Kingdom
| | - Xing Chang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhiming Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ruxiu Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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Reyat JS, Sommerfeld LC, O’Reilly M, Roth Cardoso V, Thiemann E, Khan AO, O’Shea C, Harder S, Müller C, Barlow J, Stapley RJ, Chua W, Kabir SN, Grech O, Hummel O, Hübner N, Kääb S, Mont L, Hatem SN, Winters J, Zeemering S, Morgan NV, Rayes J, Gehmlich K, Stoll M, Brand T, Schweizer M, Piasecki A, Schotten U, Gkoutos GV, Lorenz K, Cuello F, Kirchhof P, Fabritz L. PITX2 deficiency leads to atrial mitochondrial dysfunction. Cardiovasc Res 2024; 120:1907-1923. [PMID: 39129206 PMCID: PMC11630043 DOI: 10.1093/cvr/cvae169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 04/27/2024] [Accepted: 05/23/2024] [Indexed: 08/13/2024] Open
Abstract
AIMS Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation (AF). PITX2 is restricted to left atrial cardiomyocytes (aCMs) in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy, and AF are not fully understood. METHODS AND RESULTS To identify mechanisms linking PITX2 deficiency to AF, we generated and characterized PITX2-deficient human aCMs derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganized sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared with isogenic controls. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with AF compared with 43 patients with sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. CONCLUSION PITX2 deficiency causes atrial mitochondrial dysfunction and a metabolic shift to glycolysis in human aCMs. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.
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Affiliation(s)
- Jasmeet S Reyat
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK
| | - Laura C Sommerfeld
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
- Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- University Center of Cardiovascular Sciences, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - Molly O’Reilly
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
| | - Victor Roth Cardoso
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
- Institute of Cancer Genomics, College of Medical and Dental Sciences, University of Birmingham, B15 2TT Birmingham, UK
| | - Ellen Thiemann
- Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Abdullah O Khan
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
| | - Christopher O’Shea
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
| | - Sönke Harder
- Institut für Klinische Chemie und Laboratoriumsmedizin, Massenspektrometrische Proteomanalytik, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Christian Müller
- UKE Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Jonathan Barlow
- Cellular Health and Metabolism Facility, College of Life and Environmental Sciences, University of Birmingham, B15 2TT Birmingham, UK
| | - Rachel J Stapley
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
| | - Winnie Chua
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
| | - S Nashitha Kabir
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
| | - Olivia Grech
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
| | - Oliver Hummel
- Max Delbrück Centrum for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
| | - Norbert Hübner
- Max Delbrück Centrum for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
- Charite—Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Germany
| | - Stefan Kääb
- Department of Medicine I, University Hospital Munich, Ludwig Maximilian University of Munich (LMU), Marchioninistraße 15, 81377 Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Lluis Mont
- Hospital Clínic, Universitat de Barcelona, Villarroel, 170, 08036, Barcelona, Catalonia, Spain
- Institut de Recerca Biomèdica, August Pi- i Sunyer, Roselló, 149-153, 08036 Barcelona, Catalonia, Spain
- Centro Investigación Biomedica en Red Cardiovascular, Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, 28029 Madrid, Spain
| | - Stéphane N Hatem
- INSERM UMRS1166, ICAN—Institute of Cardiometabolism and Nutrition, Sorbonne University, Institute of Cardiology, Pitié-Salpêtrière Hospital, 91 Boulevard de l’Hôpital, 75013 Paris, France
| | - Joris Winters
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Minderbroedersberg 4-66211 LK Maastricht, The Netherlands
| | - Stef Zeemering
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Minderbroedersberg 4-66211 LK Maastricht, The Netherlands
| | - Neil V Morgan
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
| | - Julie Rayes
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
| | - Katja Gehmlich
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
| | - Monika Stoll
- Institute of Human Genetics, Genetic Epidemiology, WWU Münster, Albert-Schweitzer-Campus 1, D3, Domagkstraße 3, 48149 Münster, Germany
- Cardiovascular Research Institute Maastricht, Genetic Epidemiology and Statistical Genetics, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
| | - Theresa Brand
- Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Straße 9, 97078 Würzburg, Germany
| | - Michaela Schweizer
- Department of Morphology and Electron Microscopy, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - Angelika Piasecki
- Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Ulrich Schotten
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Minderbroedersberg 4-66211 LK Maastricht, The Netherlands
| | - Georgios V Gkoutos
- Institute of Cancer Genomics, College of Medical and Dental Sciences, University of Birmingham, B15 2TT Birmingham, UK
| | - Kristina Lorenz
- Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Straße 9, 97078 Würzburg, Germany
- Leibniz-Institut für Analytische Wissenschaften—ISAS—e.V., ISAS City, Bunsen-Kirchhoff-Straße 11, 44139 Dortmund, Germany
| | - Friederike Cuello
- DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Paulus Kirchhof
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
- Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - Larissa Fabritz
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Wolfson Drive, B15 2TT Birmingham, UK
- Department of Cardiology, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- University Center of Cardiovascular Sciences, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
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4
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Baudic M, Murata H, Bosada FM, Melo US, Aizawa T, Lindenbaum P, van der Maarel LE, Guedon A, Baron E, Fremy E, Foucal A, Ishikawa T, Ushinohama H, Jurgens SJ, Choi SH, Kyndt F, Le Scouarnec S, Wakker V, Thollet A, Rajalu A, Takaki T, Ohno S, Shimizu W, Horie M, Kimura T, Ellinor PT, Petit F, Dulac Y, Bru P, Boland A, Deleuze JF, Redon R, Le Marec H, Le Tourneau T, Gourraud JB, Yoshida Y, Makita N, Vieyres C, Makiyama T, Mundlos S, Christoffels VM, Probst V, Schott JJ, Barc J. TAD boundary deletion causes PITX2-related cardiac electrical and structural defects. Nat Commun 2024; 15:3380. [PMID: 38643172 PMCID: PMC11032321 DOI: 10.1038/s41467-024-47739-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 04/08/2024] [Indexed: 04/22/2024] Open
Abstract
While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.
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Affiliation(s)
- Manon Baudic
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Hiroshige Murata
- The Department of Cardiovascular Medicine, Nippon Medical School Hospital, Tokyo, Japan
| | - Fernanda M Bosada
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | - Uirá Souto Melo
- Max Planck Institute for Molecular Genetics, RG Development and Disease, 13353, Berlin, Germany
| | - Takanori Aizawa
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Pierre Lindenbaum
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Lieve E van der Maarel
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | - Amaury Guedon
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Estelle Baron
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Enora Fremy
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Adrien Foucal
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Taisuke Ishikawa
- Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Hiroya Ushinohama
- Department of Cardiology, Fukuoka Children's Hospital, Fukuoka, Japan
| | - Sean J Jurgens
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
| | - Seung Hoan Choi
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Florence Kyndt
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Solena Le Scouarnec
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Vincent Wakker
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | - Aurélie Thollet
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Annabelle Rajalu
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Tadashi Takaki
- Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
- Takeda-CiRA Joint Program for iPS Cell Applications, Fujisawa, Japan
- Department of Pancreatic Islet Cell Transplantation, National Center for Global Health and Medicine, Tokyo, Japan
| | - Seiko Ohno
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
| | - Wataru Shimizu
- The Department of Cardiovascular Medicine, Nippon Medical School Hospital, Tokyo, Japan
| | - Minoru Horie
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Ohtsu, Japan
| | - Takeshi Kimura
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Patrick T Ellinor
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA
| | - Florence Petit
- Service de Génétique Clinique, CHU Lille, Hôpital Jeanne de Flandre, F-59000, Lille, France
- University of Lille, EA 7364-RADEME, F-59000, Lille, France
| | - Yves Dulac
- Unité de Cardiologie Pédiatrique, Hôpital des Enfants, F-31000, Toulouse, France
| | - Paul Bru
- Service de Cardiologie, GH La Rochelle, F-17019, La Rochelle, France
| | - Anne Boland
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France
| | - Jean-François Deleuze
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France
| | - Richard Redon
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Hervé Le Marec
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Thierry Le Tourneau
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
| | - Jean-Baptiste Gourraud
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart, Amsterdam, The Netherlands
| | - Yoshinori Yoshida
- Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Naomasa Makita
- Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Japan
- Department of Cardiology, Sapporo Teishinkai Hospital, Sapporo, Japan
| | - Claude Vieyres
- Cabinet Cardiologique, Clinique St. Joseph, F-16000, Angoulême, France
| | - Takeru Makiyama
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Department of Community Medicine Supporting System, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Stephan Mundlos
- Max Planck Institute for Molecular Genetics, RG Development and Disease, 13353, Berlin, Germany
| | - Vincent M Christoffels
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction and Development, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
| | - Vincent Probst
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart, Amsterdam, The Netherlands
| | - Jean-Jacques Schott
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart, Amsterdam, The Netherlands.
| | - Julien Barc
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du Thorax, F-44000, Nantes, France.
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart, Amsterdam, The Netherlands.
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Jiang Y, Peng Y, Tian Q, Cheng Z, Feng B, Hu J, Xia L, Guo H, Xia K, Zhou L, Hu Z. Intergenic sequences harboring potential enhancer elements contribute to Axenfeld-Rieger syndrome by regulating PITX2. JCI Insight 2024; 9:e177032. [PMID: 38592784 PMCID: PMC11141933 DOI: 10.1172/jci.insight.177032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 03/27/2024] [Indexed: 04/11/2024] Open
Abstract
Recent studies have uncovered that noncoding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity. However, how these genomic regions are functionally and structurally associated with ARS is still unclear. In this study, we performed genome-wide linkage analysis and whole-genome sequencing in a Chinese family with ARS and identified a heterozygous deletion of about 570 kb (termed LOH-1) in the intergenic sequence between paired-like homeodomain transcription factor 2 (PITX2) and family with sequence similarity 241 member A. Knockout of LOH-1 homologous sequences caused ARS phenotypes in mice. RNA-Seq and real-time quantitative PCR revealed a significant reduction in Pitx2 gene expression in LOH-1-/- mice, while forkhead box C1 expression remained unchanged. ChIP-Seq and bioinformatics analysis identified a potential enhancer region (LOH-E1) within LOH-1. Deletion of LOH-E1 led to a substantial downregulation of the PITX2 gene. Mechanistically, we found a sequence (hg38 chr4:111,399,594-111,399,691) that is on LOH-E1 could regulate PITX2 by binding to RAD21, a critical component of the cohesin complex. Knockdown of RAD21 resulted in reduced PITX2 expression. Collectively, our findings indicate that a potential enhancer sequence that is within LOH-1 may regulate PITX2 expression remotely through cohesin-mediated loop domains, leading to ARS when absent.
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Affiliation(s)
- Yizheng Jiang
- MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences and
| | - Yu Peng
- Department of Medical Genetics, The Affiliated Children’s Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Qi Tian
- MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences and
| | - Zhe Cheng
- MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences and
| | - Bei Feng
- MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences and
| | - Junping Hu
- MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences and
| | - Lu Xia
- MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences and
| | - Hui Guo
- MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences and
| | - Kun Xia
- MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences and
- MOE Key Laboratory of Rare Pediatric Diseases, Hengyang Medical School, University of South China, Hengyang, China
| | - Liang Zhou
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zhengmao Hu
- MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences and
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6
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Zhou M, Wang K, Jin Y, Liu J, Wang Y, Xue Y, Liu H, Chen Q, Cao Z, Jia X, Rui Y. Explore novel molecular mechanisms of FNDC5 in ischemia-reperfusion (I/R) injury by analyzing transcriptome changes in mouse model of skeletal muscle I/R injury with FNDC5 knockout. Cell Signal 2024; 113:110959. [PMID: 37918465 DOI: 10.1016/j.cellsig.2023.110959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/18/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND Irisin, a myokine derived from proteolytic cleavage of the fibronectin type III domain-containing protein 5 (FNDC5) protein, is crucial in protecting tissues and organs from ischemia-reperfusion (I/R) injury. However, the underlying mechanism of its action remains elusive. In this study, we investigated the expression patterns of genes associated with FNDC5 knockout to gain insights into its molecular functions. METHODS We employed a mouse model of skeletal muscle I/R injury with FNDC5 knockout to examine the transcriptional profiles using RNA sequencing. Differentially expressed genes (DEGs) were identified and subjected to further analyses, including gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein-protein interaction (PPI) network analysis, and miRNA-transcription factor network analysis. The bioinformatics findings were validated using qRT-PCR and Western blotting. RESULTS Comparative analysis of skeletal muscle transcriptomes between wild-type (WT; C57BL/6), WT-I/R, FNDC5 knockout (KO), and KO-I/R mice highlighted the significance of FNDC5 in both physiological conditions and I/R injury. Through PPI network analysis, we identified seven key genes (Col6a2, Acta2, Col4a5, Fap, Enpep, Mmp11, and Fosl1), which facilitated the construction of a TF-hub genes-miRNA regulatory network. Additionally, our results suggested that the PI3K-Akt pathway is predominantly involved in FNDC5 deletion-mediated I/R injury in skeletal muscle. Animal studies revealed reduced FNDC5 expression in skeletal muscle following I/R injury, and the gastrocnemius muscle with FNDC5 knockout exhibited larger infarct size and more severe tissue damage after I/R. Moreover, Western blot analysis confirmed the upregulation of Col6a2, Enpep, and Mmp11 protein levels following I/R, particularly in the KO-I/R group. Furthermore, FNDC5 deletion inhibited the PI3K-Akt signaling pathway. CONCLUSION This study demonstrates that FNDC5 deletion exacerbates skeletal muscle I/R injury, potentially involving the upregulation of Col6a2, Enpep, and Mmp11. Additionally, the findings suggest the involvement of the PI3K-Akt pathway in FNDC5 deletion-mediated skeletal muscle I/R injury, providing novel insights into the molecular mechanisms underlying FNDC5's role in this pathological process.
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Affiliation(s)
- Ming Zhou
- Suzhou Medical College of Soochow University, Suzhou, China; Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi 214000, China.
| | - Kai Wang
- Suzhou Medical College of Soochow University, Suzhou, China; Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi 214000, China
| | - Yesheng Jin
- Suzhou Medical College of Soochow University, Suzhou, China; Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi 214000, China
| | - Jinquan Liu
- Suzhou Medical College of Soochow University, Suzhou, China; Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi 214000, China
| | - Yapeng Wang
- Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi 214000, China
| | - Yuan Xue
- Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi 214000, China
| | - Hao Liu
- Suzhou Medical College of Soochow University, Suzhou, China; Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi 214000, China
| | - Qun Chen
- Suzhou Medical College of Soochow University, Suzhou, China
| | - Zhihai Cao
- Suzhou Medical College of Soochow University, Suzhou, China; Department of Emergency, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China
| | - Xueyuan Jia
- Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi 214000, China
| | - Yongjun Rui
- Suzhou Medical College of Soochow University, Suzhou, China; Department of Orthopaedics, Wuxi Ninth People's Hospital Affiliated to Soochow University, Wuxi 214000, China.
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Jonker T, Barnett P, Boink GJJ, Christoffels VM. Role of Genetic Variation in Transcriptional Regulatory Elements in Heart Rhythm. Cells 2023; 13:4. [PMID: 38201209 PMCID: PMC10777909 DOI: 10.3390/cells13010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 01/12/2024] Open
Abstract
Genetic predisposition to cardiac arrhythmias has been a field of intense investigation. Research initially focused on rare hereditary arrhythmias, but over the last two decades, the role of genetic variation (single nucleotide polymorphisms) in heart rate, rhythm, and arrhythmias has been taken into consideration as well. In particular, genome-wide association studies have identified hundreds of genomic loci associated with quantitative electrocardiographic traits, atrial fibrillation, and less common arrhythmias such as Brugada syndrome. A significant number of associated variants have been found to systematically localize in non-coding regulatory elements that control the tissue-specific and temporal transcription of genes encoding transcription factors, ion channels, and other proteins. However, the identification of causal variants and the mechanism underlying their impact on phenotype has proven difficult due to the complex tissue-specific, time-resolved, condition-dependent, and combinatorial function of regulatory elements, as well as their modest conservation across different model species. In this review, we discuss research efforts aimed at identifying and characterizing-trait-associated variant regulatory elements and the molecular mechanisms underlying their impact on heart rate or rhythm.
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Affiliation(s)
- Timo Jonker
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands; (T.J.); (P.B.); (G.J.J.B.)
| | - Phil Barnett
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands; (T.J.); (P.B.); (G.J.J.B.)
| | - Gerard J. J. Boink
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands; (T.J.); (P.B.); (G.J.J.B.)
- Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands
| | - Vincent M. Christoffels
- Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands; (T.J.); (P.B.); (G.J.J.B.)
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Schulz C, Lemoine MD, Mearini G, Koivumäki J, Sani J, Schwedhelm E, Kirchhof P, Ghalawinji A, Stoll M, Hansen A, Eschenhagen T, Christ T. PITX2 Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation. Circ Arrhythm Electrophysiol 2023; 16:e011602. [PMID: 36763906 DOI: 10.1161/circep.122.011602] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
BACKGROUND Electrical remodeling in human persistent atrial fibrillation is believed to result from rapid electrical activation of the atria, but underlying genetic causes may contribute. Indeed, common gene variants in an enhancer region close to PITX2 (paired-like homeodomain transcription factor 2) are strongly associated with atrial fibrillation, but the mechanism behind this association remains unknown. This study evaluated the consequences of PITX2 deletion (PITX2-/-) in human induced pluripotent stem cell-derived atrial cardiomyocytes. METHODS CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) was used to delete PITX2 in a healthy human iPSC line that served as isogenic control. Human induced pluripotent stem cell-derived atrial cardiomyocytes were differentiated with unfiltered retinoic acid and cultured in atrial engineered heart tissue. Force and action potential were measured in atrial engineered heart tissues. Single human induced pluripotent stem cell-derived atrial cardiomyocytes were isolated from atrial engineered heart tissue for ion current measurements. RESULTS PITX2-/- atrial engineered heart tissue beats slightly slower than isogenic control without irregularity. Force was lower in PITX2-/- than in isogenic control (0.053±0.015 versus 0.131±0.017 mN, n=28/3 versus n=28/4, PITX2-/- versus isogenic control; P<0.0001), accompanied by lower expression of CACNA1C and lower L-type Ca2+ current density. Early repolarization was weaker (action potential duration at 20% repolarization; 45.5±13.2 versus 8.6±5.3 ms, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P<0.0001), and maximum diastolic potential was more negative (-78.3±3.1 versus -69.7±0.6 mV, n=18/3 versus n=12/4, PITX2-/- versus isogenic control; P=0.001), despite normal inward rectifier currents (both IK1 and IK,ACh) and carbachol-induced shortening of action potential duration. CONCLUSIONS Complete PITX2 deficiency in human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulates some findings of electrical remodeling of atrial fibrillation in the absence of fast beating, indicating that these abnormalities could be primary consequences of lower PITX2 levels.
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Affiliation(s)
- Carl Schulz
- Institute of Experimental Pharmacology and Toxicology (C.S., M.D.L., G.M., J.S., A.H., T.E., T.C.), University Medical Center Hamburg-Eppendorf, Germany
- German Center for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck (C.S., M.D.L., G.M., J.S., E.S., P.K.)
| | - Marc D Lemoine
- Institute of Experimental Pharmacology and Toxicology (C.S., M.D.L., G.M., J.S., A.H., T.E., T.C.), University Medical Center Hamburg-Eppendorf, Germany
- German Center for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck (C.S., M.D.L., G.M., J.S., E.S., P.K.)
- Department of Cardiology, University Heart and Vascular Center, Hamburg, Germany (M.D.L., A.H., P.K., T.E., T.C.)
| | - Giulia Mearini
- Institute of Experimental Pharmacology and Toxicology (C.S., M.D.L., G.M., J.S., A.H., T.E., T.C.), University Medical Center Hamburg-Eppendorf, Germany
- German Center for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck (C.S., M.D.L., G.M., J.S., E.S., P.K.)
- DiNAQOR AG, Pfäffikon, Switzerland (G.M., P.K.)
| | - Jussi Koivumäki
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Finland (J.K.)
| | - Jascha Sani
- Institute of Experimental Pharmacology and Toxicology (C.S., M.D.L., G.M., J.S., A.H., T.E., T.C.), University Medical Center Hamburg-Eppendorf, Germany
- German Center for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck (C.S., M.D.L., G.M., J.S., E.S., P.K.)
| | - Edzard Schwedhelm
- Institute of Clinical Pharmacology and Toxicology (E.S.), University Medical Center Hamburg-Eppendorf, Germany
- German Center for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck (C.S., M.D.L., G.M., J.S., E.S., P.K.)
| | - Paulus Kirchhof
- German Center for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck (C.S., M.D.L., G.M., J.S., E.S., P.K.)
- Department of Cardiology, University Heart and Vascular Center, Hamburg, Germany (M.D.L., A.H., P.K., T.E., T.C.)
- DiNAQOR AG, Pfäffikon, Switzerland (G.M., P.K.)
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, United Kingdom (P.K.)
| | - Amer Ghalawinji
- Division of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Germany (A.G., M.S.)
| | - Monika Stoll
- Division of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Germany (A.G., M.S.)
- Department of Biochemistry, CARIM School for Cardiovascular Sciences, Maastricht University, the Netherlands (M.S.)
| | - Arne Hansen
- Institute of Experimental Pharmacology and Toxicology (C.S., M.D.L., G.M., J.S., A.H., T.E., T.C.), University Medical Center Hamburg-Eppendorf, Germany
- Department of Cardiology, University Heart and Vascular Center, Hamburg, Germany (M.D.L., A.H., P.K., T.E., T.C.)
| | - Thomas Eschenhagen
- Institute of Experimental Pharmacology and Toxicology (C.S., M.D.L., G.M., J.S., A.H., T.E., T.C.), University Medical Center Hamburg-Eppendorf, Germany
- Department of Cardiology, University Heart and Vascular Center, Hamburg, Germany (M.D.L., A.H., P.K., T.E., T.C.)
| | - Torsten Christ
- Institute of Experimental Pharmacology and Toxicology (C.S., M.D.L., G.M., J.S., A.H., T.E., T.C.), University Medical Center Hamburg-Eppendorf, Germany
- Department of Cardiology, University Heart and Vascular Center, Hamburg, Germany (M.D.L., A.H., P.K., T.E., T.C.)
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9
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Ling X, Liu X, Jiang S, Fan L, Ding J. The dynamics of three-dimensional chromatin organization and phase separation in cell fate transitions and diseases. CELL REGENERATION (LONDON, ENGLAND) 2022; 11:42. [PMID: 36539553 PMCID: PMC9768101 DOI: 10.1186/s13619-022-00145-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 10/18/2022] [Indexed: 12/24/2022]
Abstract
Cell fate transition is a fascinating process involving complex dynamics of three-dimensional (3D) chromatin organization and phase separation, which play an essential role in cell fate decision by regulating gene expression. Phase separation is increasingly being considered a driving force of chromatin folding. In this review, we have summarized the dynamic features of 3D chromatin and phase separation during physiological and pathological cell fate transitions and systematically analyzed recent evidence of phase separation facilitating the chromatin structure. In addition, we discuss current advances in understanding how phase separation contributes to physical and functional enhancer-promoter contacts. We highlight the functional roles of 3D chromatin organization and phase separation in cell fate transitions, and more explorations are required to study the regulatory relationship between 3D chromatin organization and phase separation. 3D chromatin organization (shown by Hi-C contact map) and phase separation are highly dynamic and play functional roles during early embryonic development, cell differentiation, somatic reprogramming, cell transdifferentiation and pathogenetic process. Phase separation can regulate 3D chromatin organization directly, but whether 3D chromatin organization regulates phase separation remains unclear.
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Affiliation(s)
- Xiaoru Ling
- grid.12981.330000 0001 2360 039XAdvanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China ,grid.12981.330000 0001 2360 039XRNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China ,grid.12981.330000 0001 2360 039XCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China
| | - Xinyi Liu
- grid.12981.330000 0001 2360 039XAdvanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China ,grid.12981.330000 0001 2360 039XRNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China ,grid.12981.330000 0001 2360 039XCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China
| | - Shaoshuai Jiang
- grid.12981.330000 0001 2360 039XAdvanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China ,grid.12981.330000 0001 2360 039XRNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China ,grid.12981.330000 0001 2360 039XCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China
| | - Lili Fan
- grid.258164.c0000 0004 1790 3548Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong China
| | - Junjun Ding
- grid.12981.330000 0001 2360 039XAdvanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China ,grid.12981.330000 0001 2360 039XRNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China ,grid.12981.330000 0001 2360 039XCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong China ,grid.410737.60000 0000 8653 1072Department of Histology and Embryology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436 China ,grid.13291.380000 0001 0807 1581West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041 China
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10
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Zeemering S, Isaacs A, Winters J, Maesen B, Bidar E, Dimopoulou C, Guasch E, Batlle M, Haase D, Hatem SN, Kara M, Kääb S, Mont L, Sinner MF, Wakili R, Maessen J, Crijns HJGM, Fabritz L, Kirchhof P, Stoll M, Schotten U. Atrial fibrillation in the presence and absence of heart failure enhances expression of genes involved in cardiomyocyte structure, conduction properties, fibrosis, inflammation, and endothelial dysfunction. Heart Rhythm 2022; 19:2115-2124. [PMID: 36007727 DOI: 10.1016/j.hrthm.2022.08.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 07/29/2022] [Accepted: 08/16/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Little is known about genome-wide changes in the atrial transcriptome as a cause or consequence of atrial fibrillation (AF), and the effect of its common and clinically relevant comorbidity-heart failure (HF). OBJECTIVE The purpose of this study was to explore candidate disease processes for AF by investigating gene expression changes in atrial tissue samples from patients with and without AF, stratified by HF. METHODS RNA sequencing was performed in right and left atrial appendage tissue in 195 patients undergoing open heart surgery from centers participating in the CATCH-ME consortium (no history of AF, n = 91; paroxysmal AF, n = 53; persistent/permanent AF, n = 51). Analyses were stratified into patients with/without HF (n = 75/120) and adjusted for age, sex, atrial side, and a combination of clinical characteristics. RESULTS We identified 35 genes associated with persistent AF compared to patients without a history of AF, both in the presence or absence of HF (false discovery rate <0.05). These were mostly novel associations, including 13 long noncoding RNAs. Genes were involved in regulation of cardiomyocyte structure, conduction properties, fibrosis, inflammation, and endothelial dysfunction. Gene set enrichment analysis identified mainly inflammatory gene sets to be enriched in AF patients without HF, and gene sets involved in cellular respiration in AF patients with HF. CONCLUSION Analysis of atrial gene expression profiles identified numerous novel genes associated with persistent AF, in the presence or absence of HF. Interestingly, no consistent transcriptional changes were associated with paroxysmal AF, suggesting that AF-induced changes in gene expression predominate other changes.
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Affiliation(s)
- Stef Zeemering
- Department of Physiology, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, the Netherlands
| | - Aaron Isaacs
- Department of Physiology, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, the Netherlands; Maastricht Centre for Systems Biology, Maastricht University, Maastricht, the Netherlands
| | - Joris Winters
- Department of Physiology, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, the Netherlands
| | - Bart Maesen
- Department of Cardiothoracic Surgery, Maastricht University Medical Centre, University Maastricht, Maastricht, the Netherlands
| | - Elham Bidar
- Department of Cardiothoracic Surgery, Maastricht University Medical Centre, University Maastricht, Maastricht, the Netherlands
| | | | - Eduard Guasch
- Cardiovascular Institute, Hospital Clinic Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain; CIBERCV, Madrid, Spain
| | - Montserrat Batlle
- Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain; CIBERCV, Madrid, Spain
| | | | - Stéphane N Hatem
- INSERM UMRS1166, Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France; Institut de Cardiologie, Hôpital Pitié-Salpêtrière, Paris, France
| | - Mansour Kara
- Institut de Cardiologie, Hôpital Pitié-Salpêtrière, Paris, France
| | - Stefan Kääb
- Department of Medicine I, University Hospital, Munich, Germany; German Centre for Cardiovascular Research, partner site Munich Heart, Munich, Germany
| | - Lluis Mont
- European Society of Cardiology, Sophia Antipolis, France; Cardiovascular Institute, Hospital Clinic Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain; CIBERCV, Madrid, Spain
| | - Moritz F Sinner
- Department of Medicine I, University Hospital, Munich, Germany; German Centre for Cardiovascular Research, partner site Munich Heart, Munich, Germany
| | - Reza Wakili
- German Centre for Cardiovascular Research, partner site Munich Heart, Munich, Germany; Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center Essen, Essen, Germany
| | - Jos Maessen
- Maastricht Centre for Systems Biology, Maastricht University, Maastricht, the Netherlands
| | - Harry J G M Crijns
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Larissa Fabritz
- Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; Department of Cardiology, UHB and SWBH NHS Trusts, Birmingham, United Kingdom
| | - Paulus Kirchhof
- INSERM UMRS1166, Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom; University Heart and Vascular Center UKE Hamburg, Hamburg, Germany; German Center for Cardiovascular Research, partner site Hamburg/Kiel/Lübeck, Germany
| | - Monika Stoll
- Maastricht Centre for Systems Biology, Maastricht University, Maastricht, the Netherlands; Institute of Human Genetics, University of Muenster, Muenster, Germany
| | - Ulrich Schotten
- Department of Physiology, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, the Netherlands; INSERM UMRS1166, Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France.
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11
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Zhi S, Jiang B, Yu W, Li Y, Wang H, Zhou T, Li N. Identification of candidate miRNA biomarkers correlated with the prognosis of cell carcinoma and endocervical adenocarcinoma via integrated bioinformatics analysis. Am J Transl Res 2022; 14:8146-8155. [PMID: 36505295 PMCID: PMC9730082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 07/28/2022] [Indexed: 12/15/2022]
Abstract
OBJECTIVES This study was designed to explore MicroRNAs (miRNAs) associated with the prognosis of cell carcinoma and endocervical adenocarcinoma (CESC) to search for biomarkers of CESC and provide guidelines for the clinical treatment. METHODS mRNAs of CESC patients were downloaded from The Cancer Genome Atlas (TCGA), and miRNA expression and clinical data of the patients were preprocessed. Key miRNAs associated with the prognosis of cervical cancer were identified by weighted gene co-expression network (WGCNA). The corresponding target genes were intersected with differentially expressed genes (DEGs) acquired from variation analysis, and the pathways and functional enrichment of genes were analyzed. Key genes were screened by Kaplan-Meier (K-M) survival analysis. Risk models were constructed using Cox proportional hazard regression model and the Least Absolute Shrinkage and Selection Operator (LASSO) method, and the predictive value of the models was evaluated by time-associated receiver operating characteristic (ROC) curves. Finally, independent prognostic factors were identified by COX analysis. RESULTS The hsa-miR-3150b-3p associated with the prognosis of CESC was identified by WGCNA. A total of 136 target genes were differentially expressed in CESC tissue and were associated with biological processes such as phylogeny, multicellular organism development and cell development. CBX7, ENPEP, FAIM2, IGF1, NUP62CL and TSC22D3 were associated with the prognosis of CESC, and a prognostic prediction model was constructed using these six genes, which had a good predictive value for the prognosis of cervical cancer within 1, 3 and 5 years (AUC: 0.784, 0.680 and 0.683, respectively). Among them, ENPEP (hazard ratio = 1.3996, 95% confidence interval: 1.0552-1.8565) was identified as an independent prognostic factor. CONCLUSIONS In this study, a highly accurate prognostic model consisting of six gene signatures was developed to predict the prognosis of patients with cervical cancer, which provides a reference for developing individualized treatment plans for patients.
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Affiliation(s)
- Shuang Zhi
- Four Gynecological Wards, Ningbo Women & Children’s HospitalNo. 339 Liuting Street, Haishu District, Ningbo 315000, Zhejiang Province, China
| | - Bengui Jiang
- Four Gynecological Wards, Ningbo Women & Children’s HospitalNo. 339 Liuting Street, Haishu District, Ningbo 315000, Zhejiang Province, China
| | - Wenying Yu
- Diagnostic Pathology Center, Ningbo Diagnostic Pathology CenterNo. 685, Huancheng North Road East, Jiangbei District, Ningbo 315021, Zhejiang Province, China
| | - Yan Li
- Four Gynecological Wards, Ningbo Women & Children’s HospitalNo. 339 Liuting Street, Haishu District, Ningbo 315000, Zhejiang Province, China
| | - Hanjin Wang
- Four Gynecological Wards, Ningbo Women & Children’s HospitalNo. 339 Liuting Street, Haishu District, Ningbo 315000, Zhejiang Province, China
| | - Teng Zhou
- Four Gynecological Wards, Ningbo Women & Children’s HospitalNo. 339 Liuting Street, Haishu District, Ningbo 315000, Zhejiang Province, China
| | - Nan Li
- Four Gynecological Wards, Ningbo Women & Children’s HospitalNo. 339 Liuting Street, Haishu District, Ningbo 315000, Zhejiang Province, China
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12
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Cumberland MJ, Riebel LL, Roy A, O’Shea C, Holmes AP, Denning C, Kirchhof P, Rodriguez B, Gehmlich K. Basic Research Approaches to Evaluate Cardiac Arrhythmia in Heart Failure and Beyond. Front Physiol 2022; 13:806366. [PMID: 35197863 PMCID: PMC8859441 DOI: 10.3389/fphys.2022.806366] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 01/10/2022] [Indexed: 12/20/2022] Open
Abstract
Patients with heart failure often develop cardiac arrhythmias. The mechanisms and interrelations linking heart failure and arrhythmias are not fully understood. Historically, research into arrhythmias has been performed on affected individuals or in vivo (animal) models. The latter however is constrained by interspecies variation, demands to reduce animal experiments and cost. Recent developments in in vitro induced pluripotent stem cell technology and in silico modelling have expanded the number of models available for the evaluation of heart failure and arrhythmia. An agnostic approach, combining the modalities discussed here, has the potential to improve our understanding for appraising the pathology and interactions between heart failure and arrhythmia and can provide robust and validated outcomes in a variety of research settings. This review discusses the state of the art models, methodologies and techniques used in the evaluation of heart failure and arrhythmia and will highlight the benefits of using them in combination. Special consideration is paid to assessing the pivotal role calcium handling has in the development of heart failure and arrhythmia.
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Affiliation(s)
- Max J. Cumberland
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Leto L. Riebel
- Department of Computer Science, University of Oxford, Oxford, United Kingdom
| | - Ashwin Roy
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Christopher O’Shea
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Andrew P. Holmes
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Chris Denning
- Stem Cell Biology Unit, Biodiscovery Institute, British Heart Foundation Centre for Regenerative Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Paulus Kirchhof
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Blanca Rodriguez
- Department of Computer Science, University of Oxford, Oxford, United Kingdom
| | - Katja Gehmlich
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford and British Heart Foundation Centre of Research Excellence Oxford, Oxford, United Kingdom
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13
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Abstract
The Human Genome Project marked a major milestone in the scientific community as it unravelled the ~3 billion bases that are central to crucial aspects of human life. Despite this achievement, it only scratched the surface of understanding how each nucleotide matters, both individually and as part of a larger unit. Beyond the coding genome, which comprises only ~2% of the whole genome, scientists have realized that large portions of the genome, not known to code for any protein, were crucial for regulating the coding genes. These large portions of the genome comprise the 'non-coding genome'. The history of gene regulation mediated by proteins that bind to the regulatory non-coding genome dates back many decades to the 1960s. However, the original definition of 'enhancers' was first used in the early 1980s. In this Review, we summarize benchmark studies that have mapped the role of cardiac enhancers in disease and development. We highlight instances in which enhancer-localized genetic variants explain the missing link to cardiac pathogenesis. Finally, we inspire readers to consider the next phase of exploring enhancer-based gene therapy for cardiovascular disease.
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14
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Zigova M, Petrejèíková E, Blašèáková M, Kmec J, Bernasovská J, Boroòová I, Kmec M. Genetic targets in the management of atrial fibrillation in patients with cardiomyopathy. JOURNAL OF THE PRACTICE OF CARDIOVASCULAR SCIENCES 2022. [DOI: 10.4103/jpcs.jpcs_65_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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15
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García-Padilla C, Domínguez JN, Lodde V, Munk R, Abdelmohsen K, Gorospe M, Jiménez-Sábado V, Ginel A, Hove-Madsen L, Aránega AE, Franco D. Identification of atrial-enriched lncRNA Walras linked to cardiomyocyte cytoarchitecture and atrial fibrillation. FASEB J 2022; 36:e22051. [PMID: 34861058 PMCID: PMC8684585 DOI: 10.1096/fj.202100844rr] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 11/04/2021] [Accepted: 11/05/2021] [Indexed: 01/03/2023]
Abstract
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in humans. Genetic and genomic analyses have recently demonstrated that the homeobox transcription factor Pitx2 plays a fundamental role regulating expression of distinct growth factors, microRNAs and ion channels leading to morphological and molecular alterations that promote the onset of AF. Here we address the plausible contribution of long non-coding (lnc)RNAs within the Pitx2>Wnt>miRNA signaling pathway. In silico analyses of annotated lncRNAs in the vicinity of the Pitx2, Wnt8 and Wnt11 chromosomal loci identified five novel lncRNAs with differential expression during cardiac development. Importantly, three of them, Walaa, Walras, and Wallrd, are evolutionarily conserved in humans and displayed preferential atrial expression during embryogenesis. In addition, Walrad displayed moderate expression during embryogenesis but was more abundant in the right atrium. Walaa, Walras and Wallrd were distinctly regulated by Pitx2, Wnt8, and Wnt11, and Wallrd was severely elevated in conditional atrium-specific Pitx2-deficient mice. Furthermore, pro-arrhythmogenic and pro-hypertrophic substrate administration to primary cardiomyocyte cell cultures consistently modulate expression of these lncRNAs, supporting distinct modulatory roles of the AF cardiovascular risk factors in the regulation of these lncRNAs. Walras affinity pulldown assays revealed its association with distinct cytoplasmic and nuclear proteins previously involved in cardiac pathophysiology, while loss-of-function assays further support a pivotal role of this lncRNA in cytoskeletal organization. We propose that lncRNAs Walaa, Walras and Wallrd, distinctly regulated by Pitx2>Wnt>miRNA signaling and pro-arrhythmogenic and pro-hypertrophic factors, are implicated in atrial arrhythmogenesis, and Walras additionally in cardiomyocyte cytoarchitecture.
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Affiliation(s)
- Carlos García-Padilla
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Jorge N. Domínguez
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Valeria Lodde
- Laboratory of Genetics and Genomics, National Institute on Aging IRP, National Institutes of Health, Baltimore, Maryland, USA,Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Rachel Munk
- Laboratory of Genetics and Genomics, National Institute on Aging IRP, National Institutes of Health, Baltimore, Maryland, USA
| | - Kotb Abdelmohsen
- Laboratory of Genetics and Genomics, National Institute on Aging IRP, National Institutes of Health, Baltimore, Maryland, USA
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging IRP, National Institutes of Health, Baltimore, Maryland, USA
| | | | - Antonino Ginel
- Department Cardiac Surgery, Hospital de Sant Pau, Barcelona, Spain,Biomedical Research Institute IIB Sant Pau, Barcelona, Spain
| | - Leif Hove-Madsen
- CIBERCV, Barcelona, Spain,Biomedical Research Institute IIB Sant Pau, Barcelona, Spain,Biomedical Research Institute Barcelona (IIBB-CSIC), Barcelona, Spain
| | - Amelia E. Aránega
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Diego Franco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
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16
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Kahr PC, Tao G, Kadow ZA, Hill MC, Zhang M, Li S, Martin JF. A novel transgenic Cre allele to label mouse cardiac conduction system. Dev Biol 2021; 478:163-172. [PMID: 34245725 PMCID: PMC8482537 DOI: 10.1016/j.ydbio.2021.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/06/2021] [Accepted: 07/06/2021] [Indexed: 11/19/2022]
Abstract
The cardiac conduction system is a network of heterogeneous cell population that initiates and propagates electric excitations in the myocardium. Purkinje fibers, a network of specialized myocardial cells, comprise the distal end of the conduction system in the ventricles. The developmental origins of Purkinje fibers and their roles during cardiac physiology and arrhythmia have been reported. However, it is not clear if they play a role during ischemic injury and heart regeneration. Here we introduce a novel tamoxifen-inducible Cre allele that specifically labels a broad range of components in the cardiac conduction system while excludes other cardiac cell types and vital organs. Using this new allele, we investigated the cellular and molecular response of Purkinje fibers to myocardial injury. In a neonatal mouse myocardial infarction model, we observed significant increase in Purkinje cell number in regenerating myocardium. RNA-Seq analysis using laser-captured Purkinje fibers showed a unique transcriptomic response to myocardial infarction. Our finds suggest a novel role of cardiac Purkinje fibers in heart injury.
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Affiliation(s)
- Peter C Kahr
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Ge Tao
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
| | - Zachary A Kadow
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Matthew C Hill
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Min Zhang
- Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 200127 Shanghai, China
| | - Shuang Li
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - James F Martin
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Texas Heart Institute, Houston, TX 77030, USA.
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17
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Bai J, Lu Y, Zhu Y, Wang H, Yin D, Zhang H, Franco D, Zhao J. Understanding PITX2-Dependent Atrial Fibrillation Mechanisms through Computational Models. Int J Mol Sci 2021; 22:7681. [PMID: 34299303 PMCID: PMC8307824 DOI: 10.3390/ijms22147681] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/14/2021] [Accepted: 07/16/2021] [Indexed: 01/11/2023] Open
Abstract
Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. Several major mechanisms cause AF in patients, including genetic predispositions to AF development. Genome-wide association studies have identified a number of genetic variants in association with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription PITX2. Because of the inherent complexity of the human heart, experimental and basic research is insufficient for understanding the functional impacts of PITX2 variants on AF. Linking PITX2 properties to ion channels, cells, tissues, atriums and the whole heart, computational models provide a supplementary tool for achieving a quantitative understanding of the functional role of PITX2 in remodelling atrial structure and function to predispose to AF. It is hoped that computational approaches incorporating all we know about PITX2-related structural and electrical remodelling would provide better understanding into its proarrhythmic effects leading to development of improved anti-AF therapies. In the present review, we discuss advances in atrial modelling and focus on the mechanistic links between PITX2 and AF. Challenges in applying models for improving patient health are described, as well as a summary of future perspectives.
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Affiliation(s)
- Jieyun Bai
- College of Information Science and Technology, Jinan University, Guangzhou 510632, China; (Y.L.); (Y.Z.)
- Auckland Bioengineering Institute, University of Auckland, Auckland 1010, New Zealand
| | - Yaosheng Lu
- College of Information Science and Technology, Jinan University, Guangzhou 510632, China; (Y.L.); (Y.Z.)
| | - Yijie Zhu
- College of Information Science and Technology, Jinan University, Guangzhou 510632, China; (Y.L.); (Y.Z.)
| | - Huijin Wang
- College of Information Science and Technology, Jinan University, Guangzhou 510632, China; (Y.L.); (Y.Z.)
| | - Dechun Yin
- Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin 150000, China;
| | - Henggui Zhang
- Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester M13 9PL, UK;
| | - Diego Franco
- Department of Experimental Biology, University of Jaen, 23071 Jaen, Spain;
| | - Jichao Zhao
- Auckland Bioengineering Institute, University of Auckland, Auckland 1010, New Zealand
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18
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Abstract
PURPOSE OF REVIEW Atrial fibrillation is the most common sustained cardiac arrhythmia. In addition to traditional risk factors, it is increasingly recognized that a genetic component underlies atrial fibrillation development. This review aims to provide an overview of the genetic cause of atrial fibrillation and clinical applications, with a focus on recent developments. RECENT FINDINGS Genome-wide association studies have now identified around 140 genetic loci associated with atrial fibrillation. Studies into the effects of several loci and their tentative gene targets have identified novel pathways associated with atrial fibrillation development. However, further validations of causality are still needed for many implicated genes. Genetic variants at identified loci also help predict individual atrial fibrillation risk and response to different therapies. SUMMARY Continued advances in the field of genetics and molecular biology have led to significant insight into the genetic underpinnings of atrial fibrillation. Potential clinical applications of these studies include the identification of new therapeutic targets and development of genetic risk scores to optimize management of this common cardiac arrhythmia.
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Affiliation(s)
- Jitae A. Kim
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Mihail G. Chelu
- Department of Cardiology, Baylor College of Medicine, Houston, TX, USA
| | - Na Li
- Department of Medicine (Section of Cardiovascular Research), Baylor College of Medicine, Houston, TX
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX
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Victorino J, Alvarez-Franco A, Manzanares M. Functional genomics and epigenomics of atrial fibrillation. J Mol Cell Cardiol 2021; 157:45-55. [PMID: 33887329 DOI: 10.1016/j.yjmcc.2021.04.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 04/07/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023]
Abstract
Atrial fibrillation is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. Despite years of study, we still do not have a full comprehension of the molecular mechanism responsible for the disease. The recent implementation of large-scale approaches in both patient samples, population studies and animal models has helped us to broaden our knowledge on the molecular drivers responsible for AF and on the mechanisms behind disease progression. Understanding genomic and epigenomic changes that take place during chronification of AF will prove essential to design novel treatments leading to improved patient care.
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Affiliation(s)
- Jesus Victorino
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Spain
| | - Alba Alvarez-Franco
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
| | - Miguel Manzanares
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
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20
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Nattel S, Aguilar M. Do Atrial Fibrillation-Promoting Gene Variants Act by Enhancing Atrial Remodeling? JACC Clin Electrophysiol 2021; 6:1522-1524. [PMID: 33213812 DOI: 10.1016/j.jacep.2020.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 07/01/2020] [Indexed: 12/20/2022]
Affiliation(s)
- Stanley Nattel
- Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada; Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Duisburg, Germany; Institut Hospitalo Universitaire de rythmologie et de modélisation cardiaque and Fondation Bordeaux Université, Bordeaux, France.
| | - Martin Aguilar
- Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada
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21
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Bertero A, Rosa-Garrido M. Three-dimensional chromatin organization in cardiac development and disease. J Mol Cell Cardiol 2021; 151:89-105. [PMID: 33242466 PMCID: PMC11056610 DOI: 10.1016/j.yjmcc.2020.11.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 11/10/2020] [Accepted: 11/18/2020] [Indexed: 02/07/2023]
Abstract
Recent technological advancements in the field of chromatin biology have rewritten the textbook on nuclear organization. We now appreciate that the folding of chromatin in the three-dimensional space (i.e. its 3D "architecture") is non-random, hierarchical, and highly complex. While 3D chromatin structure is partially encoded in the primary sequence and thereby broadly conserved across cell types and states, a substantial portion of the genome seems to be dynamic during development or in disease. Moreover, there is growing evidence that at least some of the 3D structure of chromatin is functionally linked to gene regulation, both being modulated by and impacting on multiple nuclear processes (including DNA replication, transcription, and RNA splicing). In recent years, these new concepts have nourished several investigations about the functional role of 3D chromatin topology dynamics in the heart during development and disease. This review aims to provide a comprehensive overview of our current understanding in this field, and to discuss how this knowledge can inform further research as well as clinical practice.
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Affiliation(s)
- Alessandro Bertero
- Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, 850 Republican Street, Brotman Building, Seattle, WA 98109, USA.
| | - Manuel Rosa-Garrido
- Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, 650 Charles Young Dr, Los Angeles, CA 90095, USA.
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22
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Bai J, Zhu Y, Lo A, Gao M, Lu Y, Zhao J, Zhang H. In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues. Int J Mol Sci 2021; 22:1265. [PMID: 33514068 PMCID: PMC7866025 DOI: 10.3390/ijms22031265] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/17/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023] Open
Abstract
Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.
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Affiliation(s)
- Jieyun Bai
- Department of Electronic Engineering, College of Information Science and Technology, Jinan University, Guangzhou 510632, China;
| | - Yijie Zhu
- Department of Electronic Engineering, College of Information Science and Technology, Jinan University, Guangzhou 510632, China;
| | - Andy Lo
- Auckland Bioengineering Institute, University of Auckland, Auckland 1010, New Zealand; (A.L.); (J.Z.)
| | - Meng Gao
- Department of Computer Science and Technology, College of Electrical Engineering and Information, Northeast Agricultural University, Harbin 150030, China
| | - Yaosheng Lu
- Department of Electronic Engineering, College of Information Science and Technology, Jinan University, Guangzhou 510632, China;
| | - Jichao Zhao
- Auckland Bioengineering Institute, University of Auckland, Auckland 1010, New Zealand; (A.L.); (J.Z.)
| | - Henggui Zhang
- Biological Physics Group, School of Physics and Astronomy, The University of Manchester, Manchester M13 9PL, UK;
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Tallo CA, Duncan LH, Yamamoto AH, Slaydon JD, Arya GH, Turlapati L, Mackay TFC, Carbone MA. Heat shock proteins and small nucleolar RNAs are dysregulated in a Drosophila model for feline hypertrophic cardiomyopathy. G3 (BETHESDA, MD.) 2021; 11:jkaa014. [PMID: 33561224 PMCID: PMC7849908 DOI: 10.1093/g3journal/jkaa014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 11/16/2020] [Indexed: 11/13/2022]
Abstract
In cats, mutations in myosin binding protein C (encoded by the MYBPC3 gene) have been associated with hypertrophic cardiomyopathy (HCM). However, the molecular mechanisms linking these mutations to HCM remain unknown. Here, we establish Drosophila melanogaster as a model to understand this connection by generating flies harboring MYBPC3 missense mutations (A31P and R820W) associated with feline HCM. The A31P and R820W flies displayed cardiovascular defects in their heart rates and exercise endurance. We used RNA-seq to determine which processes are misregulated in the presence of mutant MYBPC3 alleles. Transcriptome analysis revealed significant downregulation of genes encoding small nucleolar RNA (snoRNAs) in exercised female flies harboring the mutant alleles compared to flies that harbor the wild-type allele. Other processes that were affected included the unfolded protein response and immune/defense responses. These data show that mutant MYBPC3 proteins have widespread effects on the transcriptome of co-regulated genes. Transcriptionally differentially expressed genes are also candidate genes for future evaluation as genetic modifiers of HCM as well as candidate genes for genotype by exercise environment interaction effects on the manifestation of HCM; in cats as well as humans.
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Affiliation(s)
- Christian A Tallo
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7614, USA
| | - Laura H Duncan
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7614, USA
| | - Akihiko H Yamamoto
- The Department of Entomology and Plant Pathology, North Carolina State University, Raleigh, NC 27695-7613, USA
| | - Joshua D Slaydon
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7614, USA
| | - Gunjan H Arya
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7614, USA
| | - Lavanya Turlapati
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7614, USA
| | - Trudy F C Mackay
- The Center for Human Genetics and Department of Genetics and Biochemistry, Clemson University, Greenwood, SC 29646, USA
| | - Mary A Carbone
- The Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, USA
- The Center for Integrated Fungal Research and Department of Plant and Microbial Biology, North Carolina State University, Raleigh NC 27695-7244, USA
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Tallo CA, Duncan LH, Yamamoto AH, Slaydon JD, Arya GH, Turlapati L, Mackay TFC, Carbone MA. Heat shock proteins and small nucleolar RNAs are dysregulated in a Drosophila model for feline hypertrophic cardiomyopathy. G3 (BETHESDA, MD.) 2021. [PMID: 33561224 DOI: 10.1093/g3journal/jkaa014.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
In cats, mutations in myosin binding protein C (encoded by the MYBPC3 gene) have been associated with hypertrophic cardiomyopathy (HCM). However, the molecular mechanisms linking these mutations to HCM remain unknown. Here, we establish Drosophila melanogaster as a model to understand this connection by generating flies harboring MYBPC3 missense mutations (A31P and R820W) associated with feline HCM. The A31P and R820W flies displayed cardiovascular defects in their heart rates and exercise endurance. We used RNA-seq to determine which processes are misregulated in the presence of mutant MYBPC3 alleles. Transcriptome analysis revealed significant downregulation of genes encoding small nucleolar RNA (snoRNAs) in exercised female flies harboring the mutant alleles compared to flies that harbor the wild-type allele. Other processes that were affected included the unfolded protein response and immune/defense responses. These data show that mutant MYBPC3 proteins have widespread effects on the transcriptome of co-regulated genes. Transcriptionally differentially expressed genes are also candidate genes for future evaluation as genetic modifiers of HCM as well as candidate genes for genotype by exercise environment interaction effects on the manifestation of HCM; in cats as well as humans.
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Affiliation(s)
- Christian A Tallo
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7614, USA
| | - Laura H Duncan
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7614, USA
| | - Akihiko H Yamamoto
- The Department of Entomology and Plant Pathology, North Carolina State University, Raleigh, NC 27695-7613, USA
| | - Joshua D Slaydon
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7614, USA
| | - Gunjan H Arya
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7614, USA
| | - Lavanya Turlapati
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695-7614, USA
| | - Trudy F C Mackay
- The Center for Human Genetics and Department of Genetics and Biochemistry, Clemson University, Greenwood, SC 29646, USA
| | - Mary A Carbone
- The Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27695, USA.,The Center for Integrated Fungal Research and Department of Plant and Microbial Biology, North Carolina State University, Raleigh NC 27695-7244, USA
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25
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Enhancer polymorphisms at the IKZF1 susceptibility locus for acute lymphoblastic leukemia impact B-cell proliferation and differentiation in both Down syndrome and non-Down syndrome genetic backgrounds. PLoS One 2021; 16:e0244863. [PMID: 33411777 PMCID: PMC7790404 DOI: 10.1371/journal.pone.0244863] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 12/17/2020] [Indexed: 12/26/2022] Open
Abstract
Children with Down syndrome have an approximately 10-fold increased risk of developing acute lymphoblastic leukemia and this risk is influenced by inherited genetic variation. Genome-wide association studies have identified IKZF1 as a strong acute lymphoblastic leukemia susceptibility locus in children both with and without Down syndrome, with association signals reported at rs4132601 in non-Down syndrome and rs58923657 in individuals with Down syndrome (r2 = 0.98 for these two loci). Expression quantitative trait locus analysis in non-Down syndrome lymphoblastoid cell lines has demonstrated an association between the rs4132601 risk allele and decreased IKZF1 mRNA levels. In this study, we provide further mechanistic evidence linking the region encompassing IKZF1-associated polymorphisms to pro-leukemogenic effects in both human lymphoblastoid cell lines and murine hematopoietic stem cells. CRISPR/Cas9-mediated deletion of the region encompassing the rs17133807 major allele (r2 with rs58923657 = 0.97) resulted in significant reduction of IKZF1 mRNA levels in lymphoblastoid cell lines, with a greater effect in Down syndrome versus non-Down syndrome cells. Since rs17133807 is highly conserved in mammals, we also evaluated the orthologous murine locus at rs263378223, in hematopoietic stem cells from the Dp16(1)Yey mouse model of Down syndrome as well as non-Down syndrome control mice. Homozygous deletion of the region encompassing rs263378223 resulted in significantly reduced Ikzf1 mRNA, confirming that this polymorphism maps to a strong murine Ikzf1 enhancer, and resulted in increased B-lymphoid colony growth and decreased B-lineage differentiation. Our results suggest that both the region encompassing rs17133807 and its conserved orthologous mouse locus have functional effects that may mediate increased leukemia susceptibility in both the Down syndrome and non-Down syndrome genetic backgrounds.
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26
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Oltra E. Epigenetics of muscle disorders. MEDICAL EPIGENETICS 2021:279-308. [DOI: 10.1016/b978-0-12-823928-5.00023-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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27
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Wang QC, Wang ZY. Big Data and Atrial Fibrillation: Current Understanding and New Opportunities. J Cardiovasc Transl Res 2020; 13:944-952. [PMID: 32378163 DOI: 10.1007/s12265-020-10008-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 04/16/2020] [Indexed: 10/24/2022]
Abstract
Atrial fibrillation (AF) is the most common arrhythmia with diverse etiology that remarkably relates to high morbidity and mortality. With the advancements in intensive clinical and basic research, the understanding of electrophysiological and pathophysiological mechanism, as well as treatment of AF have made huge progress. However, many unresolved issues remain, including the core mechanisms and key intervention targets. Big data approach has produced new insights into the improvement of the situation. A large amount of data have been accumulated in the field of AF research, thus using the big data to achieve prevention and precise treatment of AF may be the direction of future development. In this review, we will discuss the current understanding of big data and explore the potential applications of big data in AF research, including predictive models of disease processes, disease heterogeneity, drug safety and development, precision medicine, and the potential source for big data acquisition. Grapical abstract.
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Affiliation(s)
- Qian-Chen Wang
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, China
| | - Zhen-Yu Wang
- Department of Cardiovascular Medicine, the Second Xiangya Hospital, Central South University, No.139 Renmin Road, Changsha, Hunan, China.
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28
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Wong GR, Nalliah CJ, Lee G, Voskoboinik A, Prabhu S, Parameswaran R, Sugumar H, Anderson RD, Ling LH, McLellan A, Johnson R, Sanders P, Kistler PM, Fatkin D, Kalman JM. Genetic Susceptibility to Atrial Fibrillation Is Associated With Atrial Electrical Remodeling and Adverse Post-Ablation Outcome. JACC Clin Electrophysiol 2020; 6:1509-1521. [PMID: 33213811 DOI: 10.1016/j.jacep.2020.05.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/19/2020] [Accepted: 05/27/2020] [Indexed: 12/27/2022]
Abstract
OBJECTIVES This study sought to assess the atrial electrophysiological properties and post-ablation outcomes in patients with atrial fibrillation (AF) with and without the rs2200733 single nucleotide variant. BACKGROUND The phenotype associated with chromosome 4q25 of the AF-susceptibility locus remains unknown. METHODS In this study, 102 consecutive patients (ages 61 ± 9 years, 64% male) with paroxysmal or persistent AF were prospectively recruited prior to ablation. Patients were genotyped for rs2200733 and high-density left atrial (LA) electroanatomic maps were created using a multipolar catheter during distal coronary sinus (CS) pacing at 600 ms. Voltage, conduction velocity (CV), CV heterogeneity, and fractionated signals of 6 LA segments were determined. Arrhythmia recurrence was assessed by continuous device (51%) and Holter monitoring. RESULTS Overall, 41 patients (40%) were single nucleotide variant carriers (38 heterozygous, 3 homozygous). A mean of 2,239 ± 852 points per patient were collected. Carriers had relatively increased CV heterogeneity (45.7 ± 7.5% vs. 35.9 ± 2.3%; p < 0.001), complex signals (9.4 ± 2.9% vs 6.0 ± 1.2%; p = 0.008), regional LA slowing, or conduction block (31.7 ± 8.2% vs. 17.9 ± 1.9%; p = 0.013) particularly in the posterior and lateral walls. There were no differences in CV, voltage, atrial refractoriness, or sinus node function. At follow-up (median: 27 months; range 19 to 31 months), carriers had lower arrhythmia-free survival (51% vs. 80%; p = 0.003). On multivariable analysis, carrier status was independently associated with CV heterogeneity (p = 0.001), complex signals (p = 0.002), and arrhythmia recurrence (p = 0.019). CONCLUSIONS These data provide the first evidence that the rs2200733-tagged haplotype alters LA electrical remodeling and is a determinant of long-term outcome following AF ablation. The molecular mechanisms underpinning these changes warrant further investigation.
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Affiliation(s)
- Geoffrey R Wong
- Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - Chrishan J Nalliah
- Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - Geoffrey Lee
- Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Aleksandr Voskoboinik
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Heart Centre, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Sandeep Prabhu
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Heart Centre, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Ramanathan Parameswaran
- Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - Hariharan Sugumar
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Heart Centre, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Robert D Anderson
- Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - Liang-Han Ling
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Heart Centre, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Alex McLellan
- Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Renee Johnson
- Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia
| | - Prashanthan Sanders
- Centre for Heart Rhythm Disorders, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Peter M Kistler
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Heart Centre, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Diane Fatkin
- Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; Cardiology Department, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia; Faculty of Medicine, University of New South Wales Sydney, Kensington, New South Wales, Australia.
| | - Jonathan M Kalman
- Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
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29
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Genetics and Epigenetics of Atrial Fibrillation. Int J Mol Sci 2020; 21:ijms21165717. [PMID: 32784971 PMCID: PMC7460853 DOI: 10.3390/ijms21165717] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 07/22/2020] [Accepted: 07/27/2020] [Indexed: 12/13/2022] Open
Abstract
Atrial fibrillation (AF) is known to be the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence exponentially increases with age and could reach up to 8% in the elderly population. The management of AF is a complex issue that is addressed by extensive ongoing basic and clinical research. AF centers around different types of disturbances, including ion channel dysfunction, Ca2+-handling abnormalities, and structural remodeling. Genome-wide association studies (GWAS) have uncovered over 100 genetic loci associated with AF. Most of these loci point to ion channels, distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Recently, the discovery of post-transcriptional regulatory mechanisms, involving non-coding RNAs (especially microRNAs), DNA methylation, and histone modification, has allowed to decipher how a normal heart develops and which modifications are involved in reshaping the processes leading to arrhythmias. This review aims to provide a current state of the field regarding the identification and functional characterization of AF-related epigenetic regulatory networks
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30
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van Ouwerkerk AF, Hall AW, Kadow ZA, Lazarevic S, Reyat JS, Tucker NR, Nadadur RD, Bosada FM, Bianchi V, Ellinor PT, Fabritz L, Martin J, de Laat W, Kirchhof P, Moskowitz I, Christoffels VM. Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation. Circ Res 2020; 127:34-50. [PMID: 32717170 PMCID: PMC8315291 DOI: 10.1161/circresaha.120.316574] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Genome-wide association studies have uncovered over a 100 genetic loci associated with atrial fibrillation (AF), the most common arrhythmia. Many of the top AF-associated loci harbor key cardiac transcription factors, including PITX2, TBX5, PRRX1, and ZFHX3. Moreover, the vast majority of the AF-associated variants lie within noncoding regions of the genome where causal variants affect gene expression by altering the activity of transcription factors and the epigenetic state of chromatin. In this review, we discuss a transcriptional regulatory network model for AF defined by effector genes in Genome-wide association studies loci. We describe the current state of the field regarding the identification and function of AF-relevant gene regulatory networks, including variant regulatory elements, dose-sensitive transcription factor functionality, target genes, and epigenetic states. We illustrate how altered transcriptional networks may impact cardiomyocyte function and ionic currents that impact AF risk. Last, we identify the need for improved tools to identify and functionally test transcriptional components to define the links between genetic variation, epigenetic gene regulation, and atrial function.
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Affiliation(s)
- Antoinette F. van Ouwerkerk
- Department of Medical Biology, Amsterdam University Medical Centers, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Amelia W. Hall
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Zachary A. Kadow
- Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
- Medical Scientist Training Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Sonja Lazarevic
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA
| | - Jasmeet S. Reyat
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
| | - Nathan R. Tucker
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Masonic Medical Research Institute, Utica, NY, USA
| | - Rangarajan D. Nadadur
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA
| | - Fernanda M. Bosada
- Department of Medical Biology, Amsterdam University Medical Centers, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Valerio Bianchi
- Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands
| | - Patrick T. Ellinor
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Larissa Fabritz
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
- SWBH and UHB NHS Trusts, Birmingham, UK
| | - Jim Martin
- Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030
- Texas Heart Institute, Houston, Texas, 77030
| | - Wouter de Laat
- Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands
| | - Paulus Kirchhof
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
- SWBH and UHB NHS Trusts, Birmingham, UK
- University Heart and Vascular Center Hamburg, Hamburg, Germany
| | - Ivan Moskowitz
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, IL 60637, USA
| | - Vincent M. Christoffels
- Department of Medical Biology, Amsterdam University Medical Centers, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
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31
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Schneider-Warme F, Ravens U. Ménage à trois: single-nucleotide polymorphisms, calcium and atrial fibrillation. Cardiovasc Res 2019; 115:479-481. [PMID: 30428015 DOI: 10.1093/cvr/cvy283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Franziska Schneider-Warme
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Elsässerstr. 2Q, Freiburg Germany.,Faculty of Medicine, University of Freiburg, Hugstetter Str 55, Freiburg, Germany
| | - Ursula Ravens
- Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg - Bad Krozingen, Medical Center - University of Freiburg, Elsässerstr. 2Q, Freiburg Germany.,Faculty of Medicine, University of Freiburg, Hugstetter Str 55, Freiburg, Germany
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32
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Early sarcomere and metabolic defects in a zebrafish pitx2c cardiac arrhythmia model. Proc Natl Acad Sci U S A 2019; 116:24115-24121. [PMID: 31704768 DOI: 10.1073/pnas.1913905116] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. The major AF susceptibility locus 4q25 establishes long-range interactions with the promoter of PITX2, a transcription factor gene with critical functions during cardiac development. While many AF-linked loci have been identified in genome-wide association studies, mechanistic understanding into how genetic variants, including those at the 4q25 locus, increase vulnerability to AF is mostly lacking. Here, we show that loss of pitx2c in zebrafish leads to adult cardiac phenotypes with substantial similarities to pathologies observed in AF patients, including arrhythmia, atrial conduction defects, sarcomere disassembly, and altered cardiac metabolism. These phenotypes are also observed in a subset of pitx2c +/- fish, mimicking the situation in humans. Most notably, the onset of these phenotypes occurs at an early developmental stage. Detailed analyses of pitx2c loss- and gain-of-function embryonic hearts reveal changes in sarcomeric and metabolic gene expression and function that precede the onset of cardiac arrhythmia first observed at larval stages. We further find that antioxidant treatment of pitx2c -/- larvae significantly reduces the incidence and severity of cardiac arrhythmia, suggesting that metabolic dysfunction is an important driver of conduction defects. We propose that these early sarcomere and metabolic defects alter cardiac function and contribute to the electrical instability and structural remodeling observed in adult fish. Overall, these data provide insight into the mechanisms underlying the development and pathophysiology of some cardiac arrhythmias and importantly, increase our understanding of how developmental perturbations can predispose to functional defects in the adult heart.
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33
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Zhang M, Hill MC, Kadow ZA, Suh JH, Tucker NR, Hall AW, Tran TT, Swinton PS, Leach JP, Margulies KB, Ellinor PT, Li N, Martin JF. Long-range Pitx2c enhancer-promoter interactions prevent predisposition to atrial fibrillation. Proc Natl Acad Sci U S A 2019; 116:22692-22698. [PMID: 31636200 PMCID: PMC6842642 DOI: 10.1073/pnas.1907418116] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Genome-wide association studies found that increased risk for atrial fibrillation (AF), the most common human heart arrhythmia, is associated with noncoding sequence variants located in proximity to PITX2 Cardiomyocyte-specific epigenomic and comparative genomics uncovered 2 AF-associated enhancers neighboring PITX2 with varying conservation in mice. Chromosome conformation capture experiments in mice revealed that the Pitx2c promoter directly contacted the AF-associated enhancer regions. CRISPR/Cas9-mediated deletion of a 20-kb topologically engaged enhancer led to reduced Pitx2c transcription and AF predisposition. Allele-specific chromatin immunoprecipitation sequencing on hybrid heterozygous enhancer knockout mice revealed that long-range interaction of an AF-associated region with the Pitx2c promoter was required for maintenance of the Pitx2c promoter chromatin state. Long-range looping was mediated by CCCTC-binding factor (CTCF), since genetic disruption of the intronic CTCF-binding site caused reduced Pitx2c expression, AF predisposition, and diminished active chromatin marks on Pitx2 AF risk variants located at 4q25 reside in genomic regions possessing long-range transcriptional regulatory functions directed at PITX2.
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Affiliation(s)
- Min Zhang
- Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 200127 Shanghai, China
| | - Matthew C Hill
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030
| | - Zachary A Kadow
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030
| | - Ji Ho Suh
- Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX 77030
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030
| | - Nathan R Tucker
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02129
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142
| | - Amelia W Hall
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02129
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142
| | - Tien T Tran
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030
| | - Paul S Swinton
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030
- Texas Heart Institute, Houston, TX 77030
| | - John P Leach
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030
| | - Kenneth B Margulies
- Penn Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104
| | - Patrick T Ellinor
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02129
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142
| | - Na Li
- Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX 77030
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030
| | - James F Martin
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030;
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030
- Texas Heart Institute, Houston, TX 77030
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34
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Bai J, Lu Y, Lo A, Zhao J, Zhang H. Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling. Front Physiol 2019; 10:1314. [PMID: 31695623 PMCID: PMC6818469 DOI: 10.3389/fphys.2019.01314] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 09/30/2019] [Indexed: 12/17/2022] Open
Abstract
Functional analysis has shown that the p.Met207Val mutation was linked to atrial fibrillation and caused an increase in transactivation activity of PITX2c, which caused changes in mRNA synthesis related to ionic channels and intercellular electrical coupling. We assumed that these changes were quantitatively translated to the functional level. This study aimed to investigate the potential impact of the PITX2c p.Met207Val mutation on atrial electrical activity through multiscale computational models. The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial cell action potentials (APs) was modified to incorporate experimental data on the expected p.Met207Val mutation-induced changes in ionic channel currents (INaL, IKs, and IKr) and intercellular electrical coupling. The cell models for wild-type (WT), heterozygous (Mutant/Wild type, MT/WT), and homozygous (Mutant, MT) PITX2c cases were incorporated into homogeneous multicellular 1D and 2D tissue models. Effects of this mutation-induced remodeling were quantified as changes in AP profile, AP duration (APD) restitution, conduction velocity (CV) restitution and wavelength (WL). Temporal and spatial vulnerabilities of atrial tissue to the genesis of reentry were computed. Dynamic behaviors of re-entrant excitation waves (Life span, tip trajectory and dominant frequency) in a homogeneous 2D tissue model were characterized. Our results suggest that the PITX2c p.Met207Val mutation abbreviated atrial APD and flattened APD restitution curves. It reduced atrial CV and WL that facilitated the conduction of high rate atrial excitation waves. It increased the tissue's temporal vulnerability by increasing the vulnerable window for initiating reentry and increased the tissue spatial vulnerability by reducing the substrate size necessary to sustain reentry. In the 2D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained reentry. In conclusion, electrical and structural remodeling arising from the PITX2c p.Met207Val mutation may increase atrial susceptibility to arrhythmia due to shortened APD, reduced CV and increased tissue vulnerability, which, in combination, facilitate initiation and maintenance of re-entrant excitation waves.
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Affiliation(s)
- Jieyun Bai
- Department of Electronic Engineering, College of Information Science and Technology, Jinan University, Guangzhou, China
| | - Yaosheng Lu
- Department of Electronic Engineering, College of Information Science and Technology, Jinan University, Guangzhou, China
| | - Andy Lo
- Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
| | - Jichao Zhao
- Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
| | - Henggui Zhang
- Biological Physics Group, School of Physics & Astronomy, University of Manchester, Manchester, United Kingdom.,Pilot National Laboratory for Marine Science and Technology, Qingdao, China
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35
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Lozano-Velasco E, Garcia-Padilla C, Aránega AE, Franco D. Genetics of Atrial Fibrilation: In Search of Novel Therapeutic Targets. Cardiovasc Hematol Disord Drug Targets 2019; 19:183-194. [PMID: 30727926 DOI: 10.2174/1871529x19666190206150349] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 01/16/2019] [Accepted: 01/23/2019] [Indexed: 06/09/2023]
Abstract
Atrial fibrillation (AF) is the most frequent arrhythmogenic disease in humans, ranging from 2% in the general population and rising up to 10-12% in 80+ years. Genetic analyses of AF familiar cases have identified a series of point mutations in distinct ion channels, supporting a causative link. However, these genetic defects only explain a minority of AF patients. Genomewide association studies identified single nucleotide polymorphisms (SNPs), close to PITX2 on 4q25 chromosome, that are highly associated to AF. Subsequent GWAS studies have identified several new loci, involving additional transcription and growth factors. Furthermore, these risk 4q25 SNPs serve as surrogate biomarkers to identify AF recurrence in distinct surgical and pharmacological interventions. Experimental studies have demonstrated an intricate signalling pathway supporting a key role of the homeobox transcription factor PITX2 as a transcriptional regulator. Furthermore, cardiovascular risk factors such as hyperthyroidism, hypertension and redox homeostasis have been identified to modulate PITX2 driven gene regulatory networks. We provide herein a state-of-the-art review of the genetic bases of atrial fibrillation, our current understanding of the genetic regulatory networks involved in AF and its plausible usage for searching novel therapeutic targets.
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Affiliation(s)
- Estefanía Lozano-Velasco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Carlos Garcia-Padilla
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Amelia E Aránega
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Diego Franco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
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36
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Scherer WJ. Corneal endothelial cell density and cardiovascular mortality: A Global Survey and Correlative Meta-Analysis. Clin Anat 2018; 31:927-936. [PMID: 30168608 DOI: 10.1002/ca.23230] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 06/10/2018] [Accepted: 06/11/2018] [Indexed: 12/15/2022]
Abstract
Based on embryological commonalities between eye and heart development, a global, country-specific meta-analysis of normal, adult corneal endothelial cell density (ECD) was performed and correlated against mortality rates secondary to diseases affecting cardiac neural crest cell (CNCC)-derived cardiovascular structures. A country-specific survey of ECD was performed by searching PubMed for studies reporting ECD datasets from normal adults. All eligible datasets were assigned a country of origin. Country-specific weighted mean ECD were calculated based on dataset n. Country-specific disease mortality rates were obtained from the World Health Organization. The correlations between weighted mean ECD and mortality rates secondary to diseases affecting CNCC-derived cardiovascular structures were calculated. As controls, correlations between ECD and noncardiovascular disease mortality were examined. Pearson correlation coefficients (r) corresponding to P-value < 0.05 were considered significant. Three hundred ninety-two datasets (39,762 eyes) from 267 source-studies were assigned to 42 countries. Significant correlations were found between ECD and mortality due to coronary heart disease (r = -0.39, P = 0.011), hypertension (r = -0.33, P = 0.033), and all-cause cardiac disease (r = -0.36, P = 0.019). No significant correlations were found between ECD and mortality secondary to the control conditions: inflammatory heart disease (mesoderm-derived tissues) (r = -0.12, P = 0.45), diabetes (r = -0.13, P = 0.41), lung disease (r = -0.21, P = 0.18), liver disease (r = -0.13, P = 0.41), renal disease (r = -0.10, P = 0.53), lung cancer (r = 0.02, P = 0.90), pancreatic cancer (r = 0.24, P = 0.13), malnutrition (r = -0.07, P = 0.66), or all-cause mortality (r = 0.04, P = 0.81). Negative correlations exist between ECD and mortality due to coronary artery disease and hypertension. On a population-based level, adult ECD is correlated to mortality from certain cardiovascular diseases. Clin. Anat. 31:927-936, 2018. © 2018 Wiley Periodicals, Inc.
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Affiliation(s)
- Warren J Scherer
- Envision Eye Specialists, 1250 Belcher Rd. South, Largo, Florida 33771
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37
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Fatkin D. ETV1: A New Player in Atrial Remodeling. Circ Res 2018; 123:515-517. [PMID: 30355145 DOI: 10.1161/circresaha.118.313606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Diane Fatkin
- From the Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia (D.F.).,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington, Australia (D.F.).,Cardiology Department, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia (D.F.)
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38
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Lozano-Velasco E, Wangensteen R, Quesada A, Garcia-Padilla C, Osorio JA, Ruiz-Torres MD, Aranega A, Franco D. Hyperthyroidism, but not hypertension, impairs PITX2 expression leading to Wnt-microRNA-ion channel remodeling. PLoS One 2017; 12:e0188473. [PMID: 29194452 PMCID: PMC5711019 DOI: 10.1371/journal.pone.0188473] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 11/07/2017] [Indexed: 01/06/2023] Open
Abstract
PITX2 is a homeobox transcription factor involved in embryonic left/right signaling and more recently has been associated to cardiac arrhythmias. Genome wide association studies have pinpointed PITX2 as a major player underlying atrial fibrillation (AF). We have previously described that PITX2 expression is impaired in AF patients. Furthermore, distinct studies demonstrate that Pitx2 insufficiency leads to complex gene regulatory network remodeling, i.e. Wnt>microRNAs, leading to ion channel impairment and thus to arrhythmogenic events in mice. Whereas large body of evidences has been provided in recent years on PITX2 downstream signaling pathways, scarce information is available on upstream pathways influencing PITX2 in the context of AF. Multiple risk factors are associated to the onset of AF, such as e.g. hypertension (HTN), hyperthyroidism (HTD) and redox homeostasis impairment. In this study we have analyzed whether HTN, HTD and/or redox homeostasis impact on PITX2 and its downstream signaling pathways. Using rat models for spontaneous HTN (SHR) and experimentally-induced HTD we have observed that both cardiovascular risk factors lead to severe Pitx2 downregulation. Interesting HTD, but not SHR, leads to up-regulation of Wnt signaling as well as deregulation of multiple microRNAs and ion channels as previously described in Pitx2 insufficiency models. In addition, redox signaling is impaired in HTD but not SHR, in line with similar findings in atrial-specific Pitx2 deficient mice. In vitro cell culture analyses using gain- and loss-of-function strategies demonstrate that Pitx2, Zfhx3 and Wnt signaling influence redox homeostasis in cardiomyocytes. Thus, redox homeostasis seems to play a pivotal role in this setting, providing a regulatory feedback loop. Overall these data demonstrate that HTD, but not HTN, can impair Pitx2>>Wnt pathway providing thus a molecular link to AF.
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Affiliation(s)
- Estefanía Lozano-Velasco
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | | | - Andrés Quesada
- Department of Health Sciences, University of Jaen, Jaen, Spain
| | - Carlos Garcia-Padilla
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Julia A. Osorio
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - María Dolores Ruiz-Torres
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Amelia Aranega
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - Diego Franco
- Cardiac and Skeletal Muscle Development Group, Department of Experimental Biology, University of Jaen, Jaen, Spain
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Multiple Roles of Pitx2 in Cardiac Development and Disease. J Cardiovasc Dev Dis 2017; 4:jcdd4040016. [PMID: 29367545 PMCID: PMC5753117 DOI: 10.3390/jcdd4040016] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Revised: 10/02/2017] [Accepted: 10/03/2017] [Indexed: 12/14/2022] Open
Abstract
Cardiac development is a complex morphogenetic process initiated as bilateral cardiogenic mesoderm is specified at both sides of the gastrulating embryo. Soon thereafter, these cardiogenic cells fuse at the embryonic midline configuring a symmetrical linear cardiac tube. Left/right bilateral asymmetry is first detected in the forming heart as the cardiac tube bends to the right, and subsequently, atrial and ventricular chambers develop. Molecular signals emanating from the node confer distinct left/right signalling pathways that ultimately lead to activation of the homeobox transcription factor Pitx2 in the left side of distinct embryonic organ anlagen, including the developing heart. Asymmetric expression of Pitx2 has therefore been reported during different cardiac developmental stages, and genetic deletion of Pitx2 provided evidence of key regulatory roles of this transcription factor during cardiogenesis and thus congenital heart diseases. More recently, impaired Pitx2 function has also been linked to arrhythmogenic processes, providing novel roles in the adult heart. In this manuscript, we provide a state-of-the-art review of the fundamental roles of Pitx2 during cardiogenesis, arrhythmogenesis and its contribution to congenital heart diseases.
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40
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Fatkin D, Santiago CF, Huttner IG, Lubitz SA, Ellinor PT. Genetics of Atrial Fibrillation: State of the Art in 2017. Heart Lung Circ 2017; 26:894-901. [DOI: 10.1016/j.hlc.2017.04.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 04/18/2017] [Indexed: 12/14/2022]
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Syeda F, Kirchhof P, Fabritz L. PITX2-dependent gene regulation in atrial fibrillation and rhythm control. J Physiol 2017; 595:4019-4026. [PMID: 28217939 PMCID: PMC5471504 DOI: 10.1113/jp273123] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 01/17/2017] [Indexed: 01/15/2023] Open
Abstract
Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. There are several major mechanisms that cause AF in patients, including a genetic predisposition to develop AF. Genome-wide association studies have identified genetic variants associated with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription factor PITX2. The effect of these common gene variants on cardiac PITX2 mRNA is currently under study. PITX2 protein regulates right-left differentiation of the embryonic heart, thorax and aorta. PITX2 is expressed in the adult left atrium, but much less so in other heart chambers. Pitx2 deficiency results in electrical and structural remodelling, and impaired repair of the heart in murine models, all of which may influence AF through divergent mechanisms. PITX2 levels and single nucleotide polymorphisms on chromosome 4q25 may also be a predictor of the effectiveness of anti-arrhythmic drug therapy.
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Affiliation(s)
- Fahima Syeda
- Institute of Cardiovascular SciencesUniversity of BirminghamBirminghamUK
| | - Paulus Kirchhof
- Institute of Cardiovascular SciencesUniversity of BirminghamBirminghamUK
- Department of CardiologyUHB NHS TrustBirminghamUK
- Department of CardiologySWBTBirminghamUK
| | - Larissa Fabritz
- Institute of Cardiovascular SciencesUniversity of BirminghamBirminghamUK
- Department of CardiologyUHB NHS TrustBirminghamUK
- Department of Cardiovascular Medicine, Division of RhythmologyUniversity Hospital MünsterMünsterGermany
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42
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Holmes RS, Spradling-Reeves KD, Cox LA. Mammalian Glutamyl Aminopeptidase Genes (ENPEP) and Proteins: Comparative Studies of a Major Contributor to Arterial Hypertension. JOURNAL OF DATA MINING IN GENOMICS & PROTEOMICS 2017; 8:2. [PMID: 29900035 PMCID: PMC5995572 DOI: 10.4172/2153-0602.1000211] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Glutamyl aminopeptidase (ENPEP) is a member of the M1 family of endopeptidases which are mammalian type II integral membrane zinc-containing endopeptidases. ENPEP is involved in the catabolic pathway of the renin-angiotensin system forming angiotensin III, which participates in blood pressure regulation and blood vessel formation. Comparative ENPEP amino acid sequences and structures and ENPEP gene locations were examined using data from several mammalian genome projects. Mammalian ENPEP sequences shared 71-98% identities. Five N-glycosylation sites were conserved for all mammalian ENPEP proteins examined although 9-18 sites were observed, in each case. Sequence alignments, key amino acid residues and predicted secondary and tertiary structures were also studied, including transmembrane and cytoplasmic sequences and active site residues. Highest levels of human ENPEP expression were observed in the terminal ileum of the small intestine and in the kidney cortex. Mammalian ENPEP genes contained 20 coding exons. The human ENPEP gene promoter and first coding exon contained a CpG island (CpG27) and at least 6 transcription factor binding sites, whereas the 3'-UTR region contained 7 miRNA target sites, which may contribute to the regulation of ENPEP gene expression in tissues of the body. Phylogenetic analyses examined the relationships of mammalian ENPEP genes and proteins, including primate, other eutherian, marsupial and monotreme sources, using chicken ENPEP as a primordial sequence for comparative purposes.
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Affiliation(s)
- Roger S Holmes
- Department of Genetics and Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, USA
- Griffith Institute for Drug Design and School of Natural Sciences, Griffith University, Nathan, QLD, Australia
| | - Kimberly D Spradling-Reeves
- Department of Genetics and Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Laura A Cox
- Department of Genetics and Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, USA
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Abstract
The past 3 decades have been characterized by an exponential growth in knowledge and advances in the clinical treatment of atrial fibrillation (AF). It is now known that AF genesis requires a vulnerable atrial substrate and that the formation and composition of this substrate may vary depending on comorbid conditions, genetics, sex, and other factors. Population-based studies have identified numerous factors that modify the atrial substrate and increase AF susceptibility. To date, genetic studies have reported 17 independent signals for AF at 14 genomic regions. Studies have established that advanced age, male sex, and European ancestry are prominent AF risk factors. Other modifiable risk factors include sedentary lifestyle, smoking, obesity, diabetes mellitus, obstructive sleep apnea, and elevated blood pressure predispose to AF, and each factor has been shown to induce structural and electric remodeling of the atria. Both heart failure and myocardial infarction increase risk of AF and vice versa creating a feed-forward loop that increases mortality. Other cardiovascular outcomes attributed to AF, including stroke and thromboembolism, are well established, and epidemiology studies have championed therapeutics that mitigate these adverse outcomes. However, the role of anticoagulation for preventing dementia attributed to AF is less established. Our review is a comprehensive examination of the epidemiological data associating unmodifiable and modifiable risk factors for AF and of the pathophysiological evidence supporting the mechanistic link between each risk factor and AF genesis. Our review also critically examines the epidemiological data on clinical outcomes attributed to AF and summarizes current evidence linking each outcome with AF.
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Affiliation(s)
- Laila Staerk
- Cardiovascular Research Centre, Herlev and Gentofte University Hospital, Copenhagen, Denmark
- Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, United States
- Boston University and National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, United States
| | - Jason A. Sherer
- Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
| | - Darae Ko
- Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, United States
- Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States
- Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
| | - Emelia J. Benjamin
- Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, United States
- Boston University and National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, United States
- Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States
- Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
- Section of Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
| | - Robert H. Helm
- Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
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44
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Wang X, Shan X, Gregory-Evans CY. A mouse model of aniridia reveals the in vivo downstream targets of Pax6 driving iris and ciliary body development in the eye. Biochim Biophys Acta Mol Basis Dis 2017; 1863:60-67. [DOI: 10.1016/j.bbadis.2016.10.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 10/13/2016] [Accepted: 10/18/2016] [Indexed: 11/28/2022]
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45
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Ye J, Tucker NR, Weng LC, Clauss S, Lubitz SA, Ellinor PT. A Functional Variant Associated with Atrial Fibrillation Regulates PITX2c Expression through TFAP2a. Am J Hum Genet 2016; 99:1281-1291. [PMID: 27866707 PMCID: PMC5142106 DOI: 10.1016/j.ajhg.2016.10.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 10/03/2016] [Indexed: 01/22/2023] Open
Abstract
The most significantly associated genetic locus for atrial fibrillation (AF) is in chromosomal region 4q25, where four independent association signals have been identified. Although model-system studies suggest that altered PITX2c expression might underlie the association, the link between specific variants and the direction of effect on gene expression remains unknown for all four signals. In the present study, we analyzed the AF-associated region most proximal to PITX2 at 4q25. First, we identified candidate regulatory variants that might confer AF risk through a combination of mammalian conservation, DNase hypersensitivity, and histone modification from ENCODE and the Roadmap Epigenomics Project, as well as through in vivo analysis of enhancer activity in embryonic zebrafish. Within candidate regions, we then identified a single associated SNP, rs2595104, which displayed dramatically reduced enhancer activity with the AF risk allele. CRISPR-Cas9-mediated deletion of the rs2595104 region and editing of the rs2595104 risk allele in human stem-cell-derived cardiomyocytes resulted in diminished PITX2c expression in comparison to that of the non-risk allele. This differential activity was mediated by activating enhancer binding protein 2 alpha (TFAP2a), which bound robustly to the non-risk allele at rs2595104, but not to the risk allele, in cardiomyocytes. In sum, we found that the AF-associated SNP rs2595104 altered PITX2c expression via interaction with TFAP2a. Such a pathway could ultimately contribute to AF susceptibility at the PITX2 locus associated with AF.
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Affiliation(s)
- Jiangchuan Ye
- Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Nathan R Tucker
- Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Lu-Chen Weng
- Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Sebastian Clauss
- Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Steven A Lubitz
- Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Patrick T Ellinor
- Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
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46
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Slagle CE, Conlon FL. Emerging Field of Cardiomics: High-Throughput Investigations into Transcriptional Regulation of Cardiovascular Development and Disease. Trends Genet 2016; 32:707-716. [PMID: 27717505 DOI: 10.1016/j.tig.2016.09.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/25/2016] [Accepted: 09/01/2016] [Indexed: 01/19/2023]
Abstract
Congenital heart defects remain a leading cause of infant mortality in the western world, despite decades of research focusing on cardiovascular development and disease. With the recent emergence of several high-throughput technologies including RNA sequencing, chromatin-immunoprecipitation-coupled sequencing, mass-spectrometry-based proteomics analyses, and the numerous variations of these strategies, investigations into cardiac development have been transformed from candidate-based studies into whole-genome, -transcriptome, and -proteome undertakings. In this review, we discuss several reports that have emerged from our laboratory and others over the past 5 years that emphasize the versatility of large dataset-based investigations of cardiogenic transcription factors, from phenotypic validations and new gene implications to the identification of novel roles of well-studied transcriptional regulators.
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Affiliation(s)
- Christopher E Slagle
- McAllister Heart Institute, Lineberger Comprehensive Cancer Center, Integrative Program for Biological & Genome Sciences, Departments of Biology and Genetics, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA
| | - Frank L Conlon
- McAllister Heart Institute, Lineberger Comprehensive Cancer Center, Integrative Program for Biological & Genome Sciences, Departments of Biology and Genetics, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
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47
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Babu D, Fullwood MJ. 3D genome organization in health and disease: emerging opportunities in cancer translational medicine. Nucleus 2016; 6:382-93. [PMID: 26553406 PMCID: PMC4915485 DOI: 10.1080/19491034.2015.1106676] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Organizing the DNA to fit inside a spatially constrained nucleus is a challenging problem that has attracted the attention of scientists across all disciplines of science. Increasing evidence has demonstrated the importance of genome geometry in several cellular contexts that affect human health. Among several approaches, the application of sequencing technologies has substantially increased our understanding of this intricate organization, also known as chromatin interactions. These structures are involved in transcriptional control of gene expression by connecting distal regulatory elements with their target genes and regulating co-transcriptional splicing. In addition, chromatin interactions play pivotal roles in the organization of the genome, the formation of structural variants, recombination, DNA replication and cell division. Mutations in factors that regulate chromatin interactions lead to the development of pathological conditions, for example, cancer. In this review, we discuss key findings that have shed light on the importance of these structures in the context of cancers, and highlight the applicability of chromatin interactions as potential biomarkers in molecular medicine as well as therapeutic implications of chromatin interactions.
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Affiliation(s)
- Deepak Babu
- a Cancer Science Institute of Singapore: Singapore; National University of Singapore ; Singapore
| | - Melissa J Fullwood
- a Cancer Science Institute of Singapore: Singapore; National University of Singapore ; Singapore.,b School of Biological Sciences; Nanyang Technological University ; Singapore.,c Institute of Molecular and Cell Biology; Agency for Science; Technology and Research (A*STAR) ; Singapore.,d Yale-NUS Liberal Arts College ; Singapore
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48
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Sun L, Tian L, Xu J, Zhang Z, Liu X. Chromosome 4q25 Variants and Age at Onset of Ischemic Stroke. Mol Neurobiol 2016; 54:3388-3394. [PMID: 27170280 DOI: 10.1007/s12035-016-9903-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 05/03/2016] [Indexed: 11/28/2022]
Abstract
Recent genome-wide association studies have identified two variants rs10033464 and rs2200733 on chromosome 4q25, significantly associated with ischemic stroke risk. We conducted this study to investigate whether these two variants were associated with age at onset and prognosis of ischemic stroke in a Chinese population. Genotyping of rs10033464 and rs2200733 was performed by improved multiple ligase detection reaction. One-way ANOVA was used to compare the mean age of ischemic stroke onset for each variant. Combined effects of these two variants on age at ischemic stroke onset were then estimated. Kaplan-Meier method, log-rank test, and the Cox proportional hazards regression models were used to assess the effect of the two variants on ischemic stroke prognosis. A total of 914 ischemic stroke patients were included in the study. Rs10033464 and rs2200733 were not associated with ischemic stroke recurrence (P > 0.05). However, rs10033464 TT genotype was significantly correlated with early age of ischemic stroke onset (60.76 for GG, 61.74 for GT, 55.47 for TT, TT vs. GT: P = 0.043). Combined effects analysis revealed that mean age at ischemic stroke onset decreased with increasing genetic risk score (P = 0.038). The findings indicated that the chromosome 4q25 variants might associate with early age at onset of ischemic stroke. Further larger studies in other populations are warranted to validate our results.
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Affiliation(s)
- Lingli Sun
- Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305# East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China
| | - Ling Tian
- Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305# East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China
| | - Jian Xu
- Molecular Oncology Research Institute, Tufts Medical Center, Tufts University, Boston, MA, USA
| | - Zhizhong Zhang
- Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305# East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China.
| | - Xinfeng Liu
- Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305# East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China.
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49
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Pérez-Hernández M, Matamoros M, Barana A, Amorós I, Gómez R, Núñez M, Sacristán S, Pinto Á, Fernández-Avilés F, Tamargo J, Delpón E, Caballero R. Pitx2c increases in atrial myocytes from chronic atrial fibrillation patients enhancing IKs and decreasing ICa,L. Cardiovasc Res 2016; 109:431-41. [PMID: 26714926 DOI: 10.1093/cvr/cvv280] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 12/15/2015] [Indexed: 11/12/2022] Open
Abstract
AIMS Atrial fibrillation (AF) produces rapid changes in the electrical properties of the atria (electrical remodelling) that promote its own recurrence. In chronic AF (CAF) patients, up-regulation of the slow delayed rectifier K(+) current (IKs) and down-regulation of the voltage-gated Ca(2+) current (ICa,L) are hallmarks of electrical remodelling and critically contribute to the abbreviation of action potential duration and atrial refractory period. Recent evidences suggested that Pitx2c, a bicoid-related homeodomain transcription factor involved in directing cardiac asymmetric morphogenesis, could play a role in atrial remodelling. However, its effects on IKs and ICa,L are unknown. METHODS AND RESULTS Real-time quantitative polymerase chain reaction analysis showed that Pitx2c mRNA expression was significantly higher in human atrial myocytes from CAF patients than those from sinus rhythm patients. The expression of Pitx2c was positively and negatively correlated with IKs and ICa,L densities, respectively. Expression of Pitx2c in HL-1 cells increased IKs density and reduced ICa,L density. Luciferase assays demonstrated that Pitx2c increased transcriptional activity of KCNQ1 and KCNE1 genes. Conversely, its effects on ICa,L could be mediated by the atrial natriuretic peptide. CONCLUSION Our results demonstrated for the first time that CAF increases Pitx2c expression in isolated human atrial myocytes and suggested that this transcription factor could contribute to the CAF-induced IKs increase and ICa,L reduction observed in humans.
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Affiliation(s)
- Marta Pérez-Hernández
- Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain
| | - Marcos Matamoros
- Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain
| | - Adriana Barana
- Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain
| | - Irene Amorós
- Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain
| | - Ricardo Gómez
- Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain
| | - Mercedes Núñez
- Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain
| | - Sandra Sacristán
- Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain
| | - Ángel Pinto
- Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid 28007, Spain
| | - Francisco Fernández-Avilés
- Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid 28007, Spain
| | - Juan Tamargo
- Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain
| | - Eva Delpón
- Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain
| | - Ricardo Caballero
- Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón, School of Medicine, Universidad Complutense, Madrid 28040, Spain
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Franco D, Lozano-Velasco E, Aranega A. Gene regulatory networks in atrial fibrillation. World J Med Genet 2016; 6:1-16. [DOI: 10.5496/wjmg.v6.i1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 12/15/2015] [Accepted: 02/17/2016] [Indexed: 02/06/2023] Open
Abstract
Atrial fibrillation (AF) is the most frequent arrhythmogenic syndrome in humans. With an estimate incidence of 1%-2% in the general population, AF raises up to almost 10%-12% in 80+ years. Thus, AF represents nowadays a highly prevalent medical problem generating a large economic burden. At the electrophysiological level, distinct mechanisms have been elucidated. Yet, despite its prevalence, the genetic and molecular culprits of this pandemic cardiac electrophysiological abnormality have remained largely obscure. Molecular genetics of AF familiar cases have demonstrated that single nucleotide mutations in distinct genes encoding for ion channels underlie the onset of AF, albeit such alterations only explain a minor subset of patients with AF. In recent years, analyses by means of genome-wide association studies have unraveled a more complex picture of the etiology of AF, pointing out to distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Furthermore a new layer of regulatory mechanisms have emerged, i.e., post-transcriptional regulation mediated by non-coding RNA, which have been demonstrated to exert pivotal roles in cardiac electrophysiology. In this manuscript, we aim to provide a comprehensive review of the genetic regulatory networks that if impaired exert electrophysiological abnormalities that contribute to the onset, and subsequently, on self-perpetuation of AF.
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