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Koch RL, Stanton JB, McClatchy S, Churchill GA, Craig SW, Williams DN, Johns ME, Chase KR, Thiesfeldt DL, Flynt JC, Pazdro R. Discovery of genomic loci for liver health and steatosis reveals overlap with glutathione redox genetics. Redox Biol 2024; 75:103248. [PMID: 38917671 PMCID: PMC11254179 DOI: 10.1016/j.redox.2024.103248] [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: 03/08/2024] [Revised: 05/27/2024] [Accepted: 06/18/2024] [Indexed: 06/27/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition in the United States, encompassing a wide spectrum of liver pathologies including steatosis, steatohepatitis, fibrosis, and cirrhosis. Despite its high prevalence, there are no medications currently approved by the Food and Drug Administration for the treatment of NAFLD. Recent work has suggested that NAFLD has a strong genetic component and identifying causative genes will improve our understanding of the molecular mechanisms contributing to NAFLD and yield targets for future therapeutic investigations. Oxidative stress is known to play an important role in NAFLD pathogenesis, yet the underlying mechanisms accounting for disturbances in redox status are not entirely understood. To better understand the relationship between the glutathione redox system and signs of NAFLD in a genetically-diverse population, we measured liver weight, serum biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and graded liver pathology in a large cohort of Diversity Outbred mice. We compared hepatic endpoints to those of the glutathione redox system previously measured in the livers and kidneys of the same mice, and we screened for statistical and genetic associations using the R/qtl2 software. We discovered several novel genetic loci associated with markers of liver health, including loci that were associated with both liver steatosis and glutathione redox status. Candidate genes within each locus point to possible new mechanisms underlying the complex relationship between NAFLD and the glutathione redox system, which could have translational implications for future studies targeting NAFLD pathology.
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Affiliation(s)
- Rebecca L Koch
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - James B Stanton
- Department of Pathology, University of Georgia, Athens, GA, USA, 30602
| | | | | | - Steven W Craig
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Darian N Williams
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Mallory E Johns
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Kylah R Chase
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Dana L Thiesfeldt
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Jessica C Flynt
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602
| | - Robert Pazdro
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA, 30602.
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2
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Baldarelli RM, Smith CL, Ringwald M, Richardson JE, Bult CJ. Mouse Genome Informatics: an integrated knowledgebase system for the laboratory mouse. Genetics 2024; 227:iyae031. [PMID: 38531069 PMCID: PMC11075557 DOI: 10.1093/genetics/iyae031] [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: 12/02/2023] [Accepted: 02/13/2024] [Indexed: 03/28/2024] Open
Abstract
Mouse Genome Informatics (MGI) is a federation of expertly curated information resources designed to support experimental and computational investigations into genetic and genomic aspects of human biology and disease using the laboratory mouse as a model system. The Mouse Genome Database (MGD) and the Gene Expression Database (GXD) are core MGI databases that share data and system architecture. MGI serves as the central community resource of integrated information about mouse genome features, variation, expression, gene function, phenotype, and human disease models acquired from peer-reviewed publications, author submissions, and major bioinformatics resources. To facilitate integration and standardization of data, biocuration scientists annotate using terms from controlled metadata vocabularies and biological ontologies (e.g. Mammalian Phenotype Ontology, Mouse Developmental Anatomy, Disease Ontology, Gene Ontology, etc.), and by applying international community standards for gene, allele, and mouse strain nomenclature. MGI serves basic scientists, translational researchers, and data scientists by providing access to FAIR-compliant data in both human-readable and compute-ready formats. The MGI resource is accessible at https://informatics.jax.org. Here, we present an overview of the core data types represented in MGI and highlight recent enhancements to the resource with a focus on new data and functionality for MGD and GXD.
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Affiliation(s)
| | | | | | | | - Carol J Bult
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
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3
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Thomas SP, Domm JM, van Vloten JP, Xu L, Vadivel A, Yates JGE, Pei Y, Ingrao J, van Lieshout LP, Jackson SR, Minott JA, Achuthan A, Mehrani Y, McAusland TM, Zhang W, Karimi K, Vaughan AE, de Jong J, Kang MH, Thebaud B, Wootton SK. A promoterless AAV6.2FF-based lung gene editing platform for the correction of surfactant protein B deficiency. Mol Ther 2023; 31:3457-3477. [PMID: 37805711 PMCID: PMC10727957 DOI: 10.1016/j.ymthe.2023.10.002] [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: 02/17/2023] [Revised: 09/07/2023] [Accepted: 10/04/2023] [Indexed: 10/09/2023] Open
Abstract
Surfactant protein B (SP-B) deficiency is a rare genetic disease that causes fatal respiratory failure within the first year of life. Currently, the only corrective treatment is lung transplantation. Here, we co-transduced the murine lung with adeno-associated virus 6.2FF (AAV6.2FF) vectors encoding a SaCas9-guide RNA nuclease or donor template to mediate insertion of promoterless reporter genes or the (murine) Sftpb gene in frame with the endogenous surfactant protein C (SP-C) gene, without disrupting SP-C expression. Intranasal administration of 3 × 1011 vg donor template and 1 × 1011 vg nuclease consistently edited approximately 6% of lung epithelial cells. Frequency of gene insertion increased in a dose-dependent manner, reaching 20%-25% editing efficiency with the highest donor template and nuclease doses tested. We next evaluated whether this promoterless gene editing platform could extend survival in the conditional SP-B knockout mouse model. Administration of 1 × 1012 vg SP-B-donor template and 5 × 1011 vg nuclease significantly extended median survival (p = 0.0034) from 5 days in the untreated off doxycycline group to 16 days in the donor AAV and nuclease group, with one gene-edited mouse living 243 days off doxycycline. This AAV6.2FF-based gene editing platform has the potential to correct SP-B deficiency, as well as other disorders of alveolar type II cells.
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Affiliation(s)
- Sylvia P Thomas
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Jakob M Domm
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Jacob P van Vloten
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Liqun Xu
- Regenerative Medicine Program, The Ottawa Hospital Research Institute (OHRI), Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO), and CHEO Research Institute, Ottawa, ON K1Y 4E9, Canada
| | - Arul Vadivel
- Regenerative Medicine Program, The Ottawa Hospital Research Institute (OHRI), Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO), and CHEO Research Institute, Ottawa, ON K1Y 4E9, Canada
| | - Jacob G E Yates
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Yanlong Pei
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Joelle Ingrao
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | | | - Sergio R Jackson
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Jessica A Minott
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Adithya Achuthan
- Regenerative Medicine Program, The Ottawa Hospital Research Institute (OHRI), Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO), and CHEO Research Institute, Ottawa, ON K1Y 4E9, Canada
| | - Yeganeh Mehrani
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Thomas M McAusland
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Wei Zhang
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada
| | - Khalil Karimi
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Andrew E Vaughan
- Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Jondavid de Jong
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Martin H Kang
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Bernard Thebaud
- Regenerative Medicine Program, The Ottawa Hospital Research Institute (OHRI), Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO), and CHEO Research Institute, Ottawa, ON K1Y 4E9, Canada
| | - Sarah K Wootton
- Department of Pathobiology, University of Guelph, Guelph, ON N1G 2W1, Canada.
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4
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Syme TE, Grill M, Hayashida E, Viengkhou B, Campbell IL, Hofer MJ. Strawberry notch homolog 2 regulates the response to interleukin-6 in the central nervous system. J Neuroinflammation 2022; 19:126. [PMID: 35624480 PMCID: PMC9145108 DOI: 10.1186/s12974-022-02475-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 05/15/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The cytokine interleukin-6 (IL-6) modulates a variety of inflammatory processes and, context depending, can mediate either pro- or anti-inflammatory effects. Excessive IL-6 signalling in the brain is associated with chronic inflammation resulting in neurodegeneration. Strawberry notch homolog 2 (Sbno2) is an IL-6-regulated gene whose function is largely unknown. Here we aimed to address this issue by investigating the impact of Sbno2 disruption in mice with IL-6-mediated neuroinflammation. METHODS Mice with germline disruption of Sbno2 (Sbno2-/-) were generated and crossed with transgenic mice with chronic astrocyte production of IL-6 (GFAP-IL6). Phenotypic, molecular and transcriptomic analyses were performed on tissues and primary cell cultures to clarify the role of SBNO2 in IL-6-mediated neuroinflammation. RESULTS We found Sbno2-/- mice to be viable and overtly normal. By contrast GFAP-IL6 × Sbno2-/- mice had more severe disease compared with GFAP-IL6 mice. This was evidenced by exacerbated neuroinflammation and neurodegeneration and enhanced IL-6-responsive gene expression. Cell culture experiments on primary astrocytes from Sbno2-/- mice further showed elevated and sustained transcript levels of a number of IL-6 stimulated genes. Notably, despite enhanced disease in vivo and gene expression both in vivo and in vitro, IL-6-stimulated gp130 pathway activation was reduced when Sbno2 is disrupted. CONCLUSION Based on these results, we propose a role for SBNO2 as a novel negative feedback regulator of IL-6 that restrains the excessive inflammatory actions of this cytokine in the brain.
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Affiliation(s)
- Taylor E Syme
- School of Life and Environmental Sciences and the Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Magdalena Grill
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010, Graz, Austria
- Division of Phoniatrics, Department of Otorhinolaryngology, Medical University of Graz, 8036, Graz, Austria
| | - Emina Hayashida
- School of Life and Environmental Sciences and the Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Barney Viengkhou
- School of Life and Environmental Sciences and the Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Iain L Campbell
- School of Life and Environmental Sciences and the Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Markus J Hofer
- School of Life and Environmental Sciences and the Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia.
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5
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Aponte JD, Katz DC, Roth DM, Vidal-García M, Liu W, Andrade F, Roseman CC, Murray SA, Cheverud J, Graf D, Marcucio RS, Hallgrímsson B. Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape. eLife 2021; 10:68623. [PMID: 34779766 PMCID: PMC8631940 DOI: 10.7554/elife.68623] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 11/12/2021] [Indexed: 12/20/2022] Open
Abstract
Realistic mappings of genes to morphology are inherently multivariate on both sides of the equation. The importance of coordinated gene effects on morphological phenotypes is clear from the intertwining of gene actions in signaling pathways, gene regulatory networks, and developmental processes underlying the development of shape and size. Yet, current approaches tend to focus on identifying and localizing the effects of individual genes and rarely leverage the information content of high-dimensional phenotypes. Here, we explicitly model the joint effects of biologically coherent collections of genes on a multivariate trait – craniofacial shape – in a sample of n = 1145 mice from the Diversity Outbred (DO) experimental line. We use biological process Gene Ontology (GO) annotations to select skeletal and facial development gene sets and solve for the axis of shape variation that maximally covaries with gene set marker variation. We use our process-centered, multivariate genotype-phenotype (process MGP) approach to determine the overall contributions to craniofacial variation of genes involved in relevant processes and how variation in different processes corresponds to multivariate axes of shape variation. Further, we compare the directions of effect in phenotype space of mutations to the primary axis of shape variation associated with broader pathways within which they are thought to function. Finally, we leverage the relationship between mutational and pathway-level effects to predict phenotypic effects beyond craniofacial shape in specific mutants. We also introduce an online application that provides users the means to customize their own process-centered craniofacial shape analyses in the DO. The process-centered approach is generally applicable to any continuously varying phenotype and thus has wide-reaching implications for complex trait genetics.
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Affiliation(s)
- Jose D Aponte
- Department of Cell Biology & Anatomy, Alberta Children's Hospital Research Institute and McCaig Bone and Joint Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - David C Katz
- Department of Cell Biology & Anatomy, Alberta Children's Hospital Research Institute and McCaig Bone and Joint Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Daniela M Roth
- School of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - Marta Vidal-García
- Department of Cell Biology & Anatomy, Alberta Children's Hospital Research Institute and McCaig Bone and Joint Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Wei Liu
- Department of Cell Biology & Anatomy, Alberta Children's Hospital Research Institute and McCaig Bone and Joint Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Fernando Andrade
- Department of Biology, Loyola University Chicago, Chicago, United States
| | - Charles C Roseman
- Department of Biology, Loyola University Chicago, Chicago, United States
| | | | - James Cheverud
- Department of Biology, Loyola University Chicago, Chicago, United States
| | - Daniel Graf
- School of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.,Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - Ralph S Marcucio
- Department of Orthopaedic Surgery, School of Medicine, University of California, San Francisco, San Francisco, United States
| | - Benedikt Hallgrímsson
- Department of Cell Biology & Anatomy, Alberta Children's Hospital Research Institute and McCaig Bone and Joint Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.,Department of Animal Biology, University of Illinois Urbana Champaign, Urbana, United States
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6
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Ringwald M, Richardson JE, Baldarelli RM, Blake JA, Kadin JA, Smith C, Bult CJ. Mouse Genome Informatics (MGI): latest news from MGD and GXD. Mamm Genome 2021; 33:4-18. [PMID: 34698891 PMCID: PMC8913530 DOI: 10.1007/s00335-021-09921-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/21/2021] [Indexed: 12/01/2022]
Abstract
The Mouse Genome Informatics (MGI) database system combines multiple expertly curated community data resources into a shared knowledge management ecosystem united by common metadata annotation standards. MGI's mission is to facilitate the use of the mouse as an experimental model for understanding the genetic and genomic basis of human health and disease. MGI is the authoritative source for mouse gene, allele, and strain nomenclature and is the primary source of mouse phenotype annotations, functional annotations, developmental gene expression information, and annotations of mouse models with human diseases. MGI maintains mouse anatomy and phenotype ontologies and contributes to the development of the Gene Ontology and Disease Ontology and uses these ontologies as standard terminologies for annotation. The Mouse Genome Database (MGD) and the Gene Expression Database (GXD) are MGI's two major knowledgebases. Here, we highlight some of the recent changes and enhancements to MGD and GXD that have been implemented in response to changing needs of the biomedical research community and to improve the efficiency of expert curation. MGI can be accessed freely at http://www.informatics.jax.org .
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7
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Gould RL, Craig SW, McClatchy S, Churchill GA, Pazdro R. Genetic mapping of renal glutathione suggests a novel regulatory locus on the murine X chromosome and overlap with hepatic glutathione regulation. Free Radic Biol Med 2021; 174:28-39. [PMID: 34324982 PMCID: PMC8597656 DOI: 10.1016/j.freeradbiomed.2021.07.035] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/14/2021] [Accepted: 07/25/2021] [Indexed: 11/29/2022]
Abstract
Glutathione (GSH) is a critical cellular antioxidant that protects against byproducts of aerobic metabolism and other reactive electrophiles to prevent oxidative stress and cell death. Proper maintenance of its reduced form, GSH, in excess of its oxidized form, GSSG, prevents oxidative stress in the kidney and protects against the development of chronic kidney disease. Evidence has indicated that renal concentrations of GSH and GSSG, as well as their ratio GSH/GSSG, are moderately heritable, and past research has identified polymorphisms and candidate genes associated with these phenotypes in mice. Yet those discoveries were made with in silico mapping methods that are prone to false positives and power limitations, so the true loci and candidate genes that control renal glutathione remain unknown. The present study utilized high-resolution gene mapping with the Diversity Outbred mouse stock to identify causal loci underlying variation in renal GSH levels and redox status. Mapping output identified a suggestive locus associated with renal GSH on murine chromosome X at 51.602 Mbp, and bioinformatic analyses identified apoptosis-inducing factor mitochondria-associated 1 (Aifm1) as the most plausible candidate. Then, mapping outputs were compiled and compared against the genetic architecture of the hepatic GSH system, and we discovered a locus on murine chromosome 14 that overlaps between hepatic GSH concentrations and renal GSH redox potential. Overall, the results support our previously proposed model that the GSH redox system is regulated by both global and tissue-specific loci, vastly improving our understanding of GSH and its regulation and proposing new candidate genes for future mechanistic studies.
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Affiliation(s)
- Rebecca L Gould
- Department of Nutritional Sciences, University of Georgia, 305 Sanford Drive, Athens, GA, 30602, USA
| | - Steven W Craig
- Department of Nutritional Sciences, University of Georgia, 305 Sanford Drive, Athens, GA, 30602, USA
| | - Susan McClatchy
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Gary A Churchill
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Robert Pazdro
- Department of Nutritional Sciences, University of Georgia, 305 Sanford Drive, Athens, GA, 30602, USA.
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8
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Gould RL, Craig SW, McClatchy S, Churchill GA, Pazdro R. Quantitative trait mapping in Diversity Outbred mice identifies novel genomic regions associated with the hepatic glutathione redox system. Redox Biol 2021; 46:102093. [PMID: 34418604 PMCID: PMC8385155 DOI: 10.1016/j.redox.2021.102093] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/24/2021] [Accepted: 08/04/2021] [Indexed: 11/01/2022] Open
Abstract
The tripeptide glutathione (GSH) is instrumental to antioxidant protection and xenobiotic metabolism, and the ratio of its reduced and oxidized forms (GSH/GSSG) indicates the cellular redox environment and maintains key aspects of cellular signaling. Disruptions in GSH levels and GSH/GSSG have long been tied to various chronic diseases, and many studies have examined whether variant alleles in genes responsible for GSH synthesis and metabolism are associated with increased disease risk. However, past studies have been limited to established, canonical GSH genes, though emerging evidence suggests that novel loci and genes influence the GSH redox system in specific tissues. The present study marks the most comprehensive effort to date to directly identify genetic loci associated with the GSH redox system. We employed the Diversity Outbred (DO) mouse population, a model of human genetics, and measured GSH and the essential redox cofactor NADPH in liver, the organ with the highest levels of GSH in the body. Under normal physiological conditions, we observed substantial variation in hepatic GSH and NADPH levels and their redox balances, and discovered a novel, significant quantitative trait locus (QTL) on murine chromosome 16 underlying GSH/GSSG; bioinformatics analyses revealed Socs1 to be the most likely candidate gene. We also discovered novel QTL associated with hepatic NADP+ levels and NADP+/NADPH, as well as unique candidate genes behind each trait. Overall, these findings transform our understanding of the GSH redox system, revealing genetic loci that govern it and proposing new candidate genes to investigate in future mechanistic endeavors.
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Affiliation(s)
- Rebecca L Gould
- Department of Nutritional Sciences, University of Georgia, 305 Sanford Drive, Athens, GA, 30602, USA
| | - Steven W Craig
- Department of Nutritional Sciences, University of Georgia, 305 Sanford Drive, Athens, GA, 30602, USA
| | - Susan McClatchy
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Gary A Churchill
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Robert Pazdro
- Department of Nutritional Sciences, University of Georgia, 305 Sanford Drive, Athens, GA, 30602, USA.
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9
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Li P, Jiang X, Zhang G, Trabucco JT, Raciti D, Smith C, Ringwald M, Marai GE, Arighi C, Shatkay H. Utilizing image and caption information for biomedical document classification. Bioinformatics 2021; 37:i468-i476. [PMID: 34252939 PMCID: PMC8346654 DOI: 10.1093/bioinformatics/btab331] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2021] [Indexed: 11/15/2022] Open
Abstract
Motivation Biomedical research findings are typically disseminated through publications. To simplify access to domain-specific knowledge while supporting the research community, several biomedical databases devote significant effort to manual curation of the literature—a labor intensive process. The first step toward biocuration requires identifying articles relevant to the specific area on which the database focuses. Thus, automatically identifying publications relevant to a specific topic within a large volume of publications is an important task toward expediting the biocuration process and, in turn, biomedical research. Current methods focus on textual contents, typically extracted from the title-and-abstract. Notably, images and captions are often used in publications to convey pivotal evidence about processes, experiments and results. Results We present a new document classification scheme, using both image and caption information, in addition to titles-and-abstracts. To use the image information, we introduce a new image representation, namely Figure-word, based on class labels of subfigures. We use word embeddings for representing captions and titles-and-abstracts. To utilize all three types of information, we introduce two information integration methods. The first combines Figure-words and textual features obtained from captions and titles-and-abstracts into a single larger vector for document representation; the second employs a meta-classification scheme. Our experiments and results demonstrate the usefulness of the newly proposed Figure-words for representing images. Moreover, the results showcase the value of Figure-words, captions and titles-and-abstracts in providing complementary information for document classification; these three sources of information when combined, lead to an overall improved classification performance. Availability and implementation Source code and the list of PMIDs of the publications in our datasets are available upon request.
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Affiliation(s)
- Pengyuan Li
- Department of Computer and Information Sciences, University of Delaware, Newark, DE 19716, USA
| | - Xiangying Jiang
- Department of Computer and Information Sciences, University of Delaware, Newark, DE 19716, USA.,Amazon, Seattle, WA 98109, USA
| | - Gongbo Zhang
- Department of Computer and Information Sciences, University of Delaware, Newark, DE 19716, USA.,Google, Mountain View, CA 94043, USA
| | - Juan Trelles Trabucco
- Department of Computer Science, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Daniela Raciti
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | | | | | - G Elisabeta Marai
- Department of Computer Science, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Cecilia Arighi
- Department of Computer and Information Sciences, University of Delaware, Newark, DE 19716, USA
| | - Hagit Shatkay
- Department of Computer and Information Sciences, University of Delaware, Newark, DE 19716, USA
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10
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da Silveira WA, Fazelinia H, Rosenthal SB, Laiakis EC, Kim MS, Meydan C, Kidane Y, Rathi KS, Smith SM, Stear B, Ying Y, Zhang Y, Foox J, Zanello S, Crucian B, Wang D, Nugent A, Costa HA, Zwart SR, Schrepfer S, Elworth RAL, Sapoval N, Treangen T, MacKay M, Gokhale NS, Horner SM, Singh LN, Wallace DC, Willey JS, Schisler JC, Meller R, McDonald JT, Fisch KM, Hardiman G, Taylor D, Mason CE, Costes SV, Beheshti A. Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact. Cell 2021; 183:1185-1201.e20. [PMID: 33242417 DOI: 10.1016/j.cell.2020.11.002] [Citation(s) in RCA: 207] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 10/01/2020] [Accepted: 11/02/2020] [Indexed: 12/11/2022]
Abstract
Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical profiles from fifty-nine astronauts and data from NASA's GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA's Twin Study provided a platform to confirm several of our principal findings. Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight.
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Affiliation(s)
| | - Hossein Fazelinia
- The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | | | | | - Man S Kim
- The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Cem Meydan
- Weill Cornell Medical College, New York, NY 10065, USA
| | - Yared Kidane
- Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA
| | - Komal S Rathi
- The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | | | - Benjamin Stear
- The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Yue Ying
- The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Yuanchao Zhang
- The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Jonathan Foox
- Weill Cornell Medical College, New York, NY 10065, USA
| | | | | | - Dong Wang
- University of California San Francisco, San Francisco, CA 94115, USA
| | | | | | - Sara R Zwart
- University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Sonja Schrepfer
- University of California San Francisco, San Francisco, CA 94115, USA
| | | | | | | | | | | | | | - Larry N Singh
- Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Douglas C Wallace
- Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | | | - Robert Meller
- Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - J Tyson McDonald
- Georgetown University Medical Center, Washington D.C. 20057, USA
| | | | - Gary Hardiman
- Queens University Belfast, Belfast BT9 5DL, UK; Medical University of South Carolina, Charleston, SC 29425, USA
| | - Deanne Taylor
- The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | | | - Afshin Beheshti
- KBR, NASA Ames Research Center, Moffett Field, CA 94035, USA.
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11
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Spevak CC, Elias HK, Kannan L, Ali MAE, Martin GH, Selvaraj S, Eng WS, Ernlund A, Rajasekhar VK, Woolthuis CM, Zhao G, Ha CJ, Schneider RJ, Park CY. Hematopoietic Stem and Progenitor Cells Exhibit Stage-Specific Translational Programs via mTOR- and CDK1-Dependent Mechanisms. Cell Stem Cell 2021; 26:755-765.e7. [PMID: 32386556 DOI: 10.1016/j.stem.2019.12.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 08/16/2019] [Accepted: 12/16/2019] [Indexed: 12/11/2022]
Abstract
Hematopoietic stem cells (HSCs) require highly regulated rates of protein synthesis, but it is unclear if they or lineage-committed progenitors preferentially recruit transcripts to translating ribosomes. We utilized polysome profiling, RNA sequencing, and whole-proteomic approaches to examine the translatome in LSK (Lin-Sca-1+c-Kit+) and myeloid progenitor (MP; Lin-Sca-1-c-Kit+) cells. Our studies show that LSKs exhibit low global translation but high translational efficiencies (TEs) of mRNAs required for HSC maintenance. In contrast, MPs activate translation in an mTOR-independent manner due, at least in part, to proteasomal degradation of mTOR by the E3 ubiquitin ligase c-Cbl. In the near absence of mTOR, CDK1 activates eIF4E-dependent translation in MPs through phosphorylation of 4E-BP1. Aberrant activation of mTOR expression and signaling in c-Cbl-deficient MPs results in increased mature myeloid lineage output. Overall, our data demonstrate that hematopoietic stem and progenitor cells (HSPCs) undergo translational reprogramming mediated by previously uncharacterized mechanisms of translational regulation.
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Affiliation(s)
- Christina C Spevak
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
| | - Harold K Elias
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
| | - Lavanya Kannan
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
| | - Mohamed A E Ali
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
| | - Gaëlle H Martin
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
| | | | - William S Eng
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
| | - Amanda Ernlund
- Department of Microbiology and Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA
| | - Vinagolu K Rajasekhar
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Carolien M Woolthuis
- Department of Hematology, Cancer Research Center, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Guangjie Zhao
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
| | - Caryn J Ha
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
| | - Robert J Schneider
- Department of Microbiology and Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA
| | - Christopher Y Park
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
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12
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Yang Y, Yao S, Ding JM, Chen W, Guo Y. Enhancer-Gene Interaction Analyses Identified the Epidermal Growth Factor Receptor as a Susceptibility Gene for Type 2 Diabetes Mellitus. Diabetes Metab J 2021; 45:241-250. [PMID: 32602275 PMCID: PMC8024152 DOI: 10.4093/dmj.2019.0204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 01/03/2020] [Indexed: 01/06/2023] Open
Abstract
Background Genetic interactions are known to play an important role in the missing heritability problem for type 2 diabetes mellitus (T2DM). Interactions between enhancers and their target genes play important roles in gene regulation and disease pathogenesis. In the present study, we aimed to identify genetic interactions between enhancers and their target genes associated with T2DM. Methods We performed genetic interaction analyses of enhancers and protein-coding genes for T2DM in 2,696 T2DM patients and 3,548 controls of European ancestry. A linear regression model was used to identify single nucleotide polymorphism (SNP) pairs that could affect the expression of the protein-coding genes. Differential expression analyses were used to identify differentially expressed susceptibility genes in diabetic and nondiabetic subjects. Results We identified one SNP pair, rs4947941×rs7785013, significantly associated with T2DM (combined P=4.84×10-10). The SNP rs4947941 was annotated as an enhancer, and rs7785013 was located in the epidermal growth factor receptor (EGFR) gene. This SNP pair was significantly associated with EGFR expression in the pancreas (P=0.033), and the minor allele "A" of rs7785013 decreased EGFR gene expression and the risk of T2DM with an increase in the dosage of "T" of rs4947941. EGFR expression was significantly upregulated in T2DM patients, which was consistent with the effect of rs4947941×rs7785013 on T2DM and EGFR expression. A functional validation study using the Mouse Genome Informatics (MGI) database showed that EGFR was associated with diabetes-relevant phenotypes. Conclusion Genetic interaction analyses of enhancers and protein-coding genes suggested that EGFR may be a novel susceptibility gene for T2DM.
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Affiliation(s)
- Yang Yang
- Clinical Laboratory, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Xi'an Center for Disease Control and Prevention, Xi'an, China
| | - Shi Yao
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Jing-Miao Ding
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Wei Chen
- Clinical Laboratory, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Yan Guo
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
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13
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Baldarelli RM, Smith CM, Finger JH, Hayamizu TF, McCright IJ, Xu J, Shaw DR, Beal JS, Blodgett O, Campbell J, Corbani LE, Frost PJ, Giannatto SC, Miers DB, Kadin JA, Richardson JE, Ringwald M. The mouse Gene Expression Database (GXD): 2021 update. Nucleic Acids Res 2021; 49:D924-D931. [PMID: 33104772 PMCID: PMC7778941 DOI: 10.1093/nar/gkaa914] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/01/2020] [Accepted: 10/02/2020] [Indexed: 01/05/2023] Open
Abstract
The Gene Expression Database (GXD; www.informatics.jax.org/expression.shtml) is an extensive and well-curated community resource of mouse developmental gene expression information. For many years, GXD has collected and integrated data from RNA in situ hybridization, immunohistochemistry, RT-PCR, northern blot, and western blot experiments through curation of the scientific literature and by collaborations with large-scale expression projects. Since our last report in 2019, we have continued to acquire these classical types of expression data; developed a searchable index of RNA-Seq and microarray experiments that allows users to quickly and reliably find specific mouse expression studies in ArrayExpress (https://www.ebi.ac.uk/arrayexpress/) and GEO (https://www.ncbi.nlm.nih.gov/geo/); and expanded GXD to include RNA-Seq data. Uniformly processed RNA-Seq data are imported from the EBI Expression Atlas and then integrated with the other types of expression data in GXD, and with the genetic, functional, phenotypic and disease-related information in Mouse Genome Informatics (MGI). This integration has made the RNA-Seq data accessible via GXD’s enhanced searching and filtering capabilities. Further, we have embedded the Morpheus heat map utility into the GXD user interface to provide additional tools for display and analysis of RNA-Seq data, including heat map visualization, sorting, filtering, hierarchical clustering, nearest neighbors analysis and visual enrichment.
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Affiliation(s)
| | | | | | - Terry F Hayamizu
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | | | - Jingxia Xu
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - David R Shaw
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Jonathan S Beal
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Olin Blodgett
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Jeffrey Campbell
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Lori E Corbani
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Pete J Frost
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | | | - Dave B Miers
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - James A Kadin
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | | | - Martin Ringwald
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
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14
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Smith CM, Kadin JA, Baldarelli RM, Beal JS, Blodgett O, Giannatto SC, Richardson JE, Ringwald M. GXD's RNA-Seq and Microarray Experiment Search: using curated metadata to reliably find mouse expression studies of interest. DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION 2021; 2020:5756137. [PMID: 32140729 PMCID: PMC7058436 DOI: 10.1093/database/baaa002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 12/09/2019] [Accepted: 01/06/2020] [Indexed: 12/28/2022]
Abstract
The Gene Expression Database (GXD), an extensive community resource of curated expression information for the mouse, has developed an RNA-Seq and Microarray Experiment Search (http://www.informatics.jax.org/gxd/htexp_index). This tool allows users to quickly and reliably find specific experiments in ArrayExpress and the Gene Expression Omnibus (GEO) that study endogenous gene expression in wild-type and mutant mice. Standardized metadata annotations, curated by GXD, allow users to specify the anatomical structure, developmental stage, mutated gene, strain and sex of samples of interest, as well as the study type and key parameters of the experiment. These searches, powered by controlled vocabularies and ontologies, can be combined with free text searching of experiment titles and descriptions. Search result summaries include link-outs to ArrayExpress and GEO, providing easy access to the expression data itself. Links to the PubMed entries for accompanying publications are also included. More information about this tool and GXD can be found at the GXD home page (http://www.informatics.jax.org/expression.shtml). Database URL:http://www.informatics.jax.org/expression.shtml
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Affiliation(s)
| | - James A Kadin
- The Jackson Laboratory 600 Main Street Bar Harbor, ME 04609, USA
| | | | - Jonathan S Beal
- The Jackson Laboratory 600 Main Street Bar Harbor, ME 04609, USA
| | - Olin Blodgett
- The Jackson Laboratory 600 Main Street Bar Harbor, ME 04609, USA
| | | | | | - Martin Ringwald
- The Jackson Laboratory 600 Main Street Bar Harbor, ME 04609, USA
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15
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Das A, Weigle AT, Arnold WR, Kim JS, Carnevale LN, Huff HC. CYP2J2 Molecular Recognition: A New Axis for Therapeutic Design. Pharmacol Ther 2020; 215:107601. [PMID: 32534953 PMCID: PMC7773148 DOI: 10.1016/j.pharmthera.2020.107601] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 05/28/2020] [Indexed: 12/11/2022]
Abstract
Cytochrome P450 (CYP) epoxygenases are a special subset of heme-containing CYP enzymes capable of performing the epoxidation of polyunsaturated fatty acids (PUFA) and the metabolism of xenobiotics. This dual functionality positions epoxygenases along a metabolic crossroad. Therefore, structure-function studies are critical for understanding their role in bioactive oxy-lipid synthesis, drug-PUFA interactions, and for designing therapeutics that directly target the epoxygenases. To better exploit CYP epoxygenases as therapeutic targets, there is a need for improved understanding of epoxygenase structure-function. Of the characterized epoxygenases, human CYP2J2 stands out as a potential target because of its role in cardiovascular physiology. In this review, the early research on the discovery and activity of epoxygenases is contextualized to more recent advances in CYP epoxygenase enzymology with respect to PUFA and drug metabolism. Additionally, this review employs CYP2J2 epoxygenase as a model system to highlight both the seminal works and recent advances in epoxygenase enzymology. Herein we cover CYP2J2's interactions with PUFAs and xenobiotics, its tissue-specific physiological roles in diseased states, and its structural features that enable epoxygenase function. Additionally, the enumeration of research on CYP2J2 identifies the future needs for the molecular characterization of CYP2J2 to enable a new axis of therapeutic design.
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Affiliation(s)
- Aditi Das
- Department of Comparative Biosciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; Center for Biophysics and Computational Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA; Department of Bioengineering, Neuroscience Program, Beckman Institute for Advanced Science and Technology, Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
| | - Austin T Weigle
- Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - William R Arnold
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Justin S Kim
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Lauren N Carnevale
- Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Hannah C Huff
- Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
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16
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Gold NB, Li D, Chassevent A, Kaiser FJ, Parenti I, Strom TM, Ramos FJ, Puisac B, Pié J, McWalter K, Guillen Sacoto MJ, Cui H, Saadeh-Haddad R, Smith-Hicks C, Rodan L, Blair E, Bhoj E. Heterozygous de novo variants in CSNK1G1 are associated with syndromic developmental delay and autism spectrum disorder. Clin Genet 2020; 98:571-576. [PMID: 33009664 DOI: 10.1111/cge.13851] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/04/2020] [Accepted: 09/15/2020] [Indexed: 11/30/2022]
Abstract
The gamma-1 isoform of casein kinase 1, the protein encoded by CSNK1G1, is involved in the growth and morphogenesis of cells. This protein is expressed ubiquitously among many tissue types, including the brain, where it regulates the phosphorylation of N-methyl-D-aspartate receptors and plays a role in synaptic transmission. One prior individual with a de novo variant in CSNK1G presenting with severe developmental delay and early-onset epilepsy has been reported. Here we report an updated clinical history of this previously published case, as well as four additional individuals with de novo variants in CSNK1G1 identified via microarray-based comparative genomic hybridization, exome, or genome sequencing. All individuals (n = 5) had developmental delay. At least three individuals had diagnoses of autism spectrum disorder. All participants were noted to have dysmorphic facial features, although the reported findings varied widely and therefore may not clearly be recognizable. None of the participants had additional major malformations. Taken together, our data suggest that CSNK1G1 may be a cause of syndromic developmental delay and possibly autism spectrum disorder.
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Affiliation(s)
- Nina B Gold
- Division of Medical Genetics and Metabolism, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts, USA
| | - Dong Li
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Anna Chassevent
- Department of Neurogenetics, The Kennedy Krieger Institute, Baltimore, Maryland, USA
| | - Frank J Kaiser
- Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | - Ilaria Parenti
- Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | - Tim M Strom
- Institute of Human Genetics, Technische Universität München, Munich, Germany.,Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Feliciano J Ramos
- Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Department of Paediatrics, Hospital "Lozano Blesa", School of Medicine, University of Zaragoza, IIS-Aragón and CIBERER-GCV02, Zaragoza, Spain
| | - Beatriz Puisac
- Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Department of Paediatrics, Hospital "Lozano Blesa", School of Medicine, University of Zaragoza, IIS-Aragón and CIBERER-GCV02, Zaragoza, Spain
| | - Juan Pié
- Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Department of Paediatrics, Hospital "Lozano Blesa", School of Medicine, University of Zaragoza, IIS-Aragón and CIBERER-GCV02, Zaragoza, Spain
| | | | | | - Hong Cui
- GeneDx Inc., Gaithersburg, Maryland, USA
| | - Reem Saadeh-Haddad
- Division of Genetics, MedStar Georgetown University Hospital Department of Pediatrics, Washington, District of Columbia, USA
| | - Constance Smith-Hicks
- Departments of Neurology and Neurogenetics, The Kennedy Krieger Institute, Baltimore, Maryland, USA
| | - Lance Rodan
- Division of Genetics and Genomics and Division of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Edward Blair
- Oxford Centre for Genomic Medicine, ACE Building, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Trust, Oxford, UK
| | - Elizabeth Bhoj
- Children's Hospital of Philadelphia, Division of Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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17
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Mistry BV, Alanazi M, Fitwi H, Al-Harazi O, Rajab M, Altorbag A, Almohanna F, Colak D, Assiri AM. Expression profiling of WD40 family genes including DDB1- and CUL4- associated factor (DCAF) genes in mice and human suggests important regulatory roles in testicular development and spermatogenesis. BMC Genomics 2020; 21:602. [PMID: 32867693 PMCID: PMC7457511 DOI: 10.1186/s12864-020-07016-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 08/20/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The WD40-repeat containing proteins, including DDB1-CUL4-associated factors (DCAFs), are abundant and conserved proteins that play important roles in different cellular processes including spermatogenesis. DCAFs are subset of WD40 family proteins that contain WDxR motif and have been proposed to function as substrate receptor for Cullin4-RING-based E3 ubiquitin ligase complexes to recruit diverse proteins for ubiquitination, a vital process in spermatogenesis. Large number of WD40 genes has been identified in different species including mouse and human. However, a systematic expression profiling of WD40 genes in different tissues of mouse and human has not been investigated. We hypothesize that large number of WD40 genes may express highly or specifically in the testis, where their expression is uniquely regulated during testis development and spermatogenesis. Therefore, the objective of this study is to mine and characterize expression patterns of WD40 genes in different tissues of mouse and human with particular emphasis on DCAF genes expressions during mouse testicular development. RESULTS Publically available RNA sequencing (RNA seq) data mining identified 347 and 349 WD40 genes in mouse and human, respectively. Hierarchical clustering and heat map analyses of RNA seq datasets revealed differential expression patterns of WD40 genes with around 60-73% of the genes were highly or specifically expressed in testis. Similarly, around 74-83% of DCAF genes were predominantly or specifically expressed in testis. Moreover, WD40 genes showed distinct expression patterns during embryonic and postnatal testis development in mice. Finally, different germ cell populations of testis showed specific patterns of WD40 genes expression. Predicted gene ontology analyses revealed more than 80% of these proteins are implicated in cellular, metabolic, biological regulation and cell localization processes. CONCLUSIONS We have identified large number of WD40 family genes that are highly or specifically expressed in the testes of mouse and human. Moreover, WD40 genes have distinct expression patterns during embryonic and postnatal development of the testis in mice. Further, different germ cell populations within the testis showed specific patterns of WD40 genes expression. These results provide foundation for further research towards understanding the functional genomics and molecular mechanisms of mammalian testis development and spermatogenesis.
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Affiliation(s)
- Bhavesh V Mistry
- Department of Comparative Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Maha Alanazi
- Department of Comparative Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Hanae Fitwi
- Department of Comparative Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Olfat Al-Harazi
- Biostatistics, Epidemiology and Scientific Computing Department, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Mohamed Rajab
- Department of Comparative Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Abdullah Altorbag
- Department of Comparative Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Falah Almohanna
- Department of Comparative Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Dilek Colak
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Abdullah M Assiri
- Department of Comparative Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. .,Biostatistics, Epidemiology and Scientific Computing Department, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. .,Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
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18
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Li P, Jiang X, Shatkay H. Figure and caption extraction from biomedical documents. Bioinformatics 2020; 35:4381-4388. [PMID: 30949681 PMCID: PMC6821181 DOI: 10.1093/bioinformatics/btz228] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 03/22/2019] [Accepted: 04/02/2019] [Indexed: 12/16/2022] Open
Abstract
Motivation Figures and captions convey essential information in biomedical documents. As such, there is a growing interest in mining published biomedical figures and in utilizing their respective captions as a source of knowledge. Notably, an essential step underlying such mining is the extraction of figures and captions from publications. While several PDF parsing tools that extract information from such documents are publicly available, they attempt to identify images by analyzing the PDF encoding and structure and the complex graphical objects embedded within. As such, they often incorrectly identify figures and captions in scientific publications, whose structure is often non-trivial. The extraction of figures, captions and figure-caption pairs from biomedical publications is thus neither well-studied nor yet well-addressed. Results We introduce a new and effective system for figure and caption extraction, PDFigCapX. Unlike existing methods, we first separate between text and graphical contents, and then utilize layout information to effectively detect and extract figures and captions. We generate files containing the figures and their associated captions and provide those as output to the end-user. We test our system both over a public dataset of computer science documents previously used by others, and over two newly collected sets of publications focusing on the biomedical domain. Our experiments and results comparing PDFigCapX to other state-of-the-art systems show a significant improvement in performance, and demonstrate the effectiveness and robustness of our approach. Availability and implementation Our system is publicly available for use at: https://www.eecis.udel.edu/~compbio/PDFigCapX. The two new datasets are available at: https://www.eecis.udel.edu/~compbio/PDFigCapX/Downloads
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Affiliation(s)
- Pengyuan Li
- Department of Computer and Information Sciences, University of Delaware, Newark, DE, USA
| | - Xiangying Jiang
- Department of Computer and Information Sciences, University of Delaware, Newark, DE, USA
| | - Hagit Shatkay
- Department of Computer and Information Sciences, University of Delaware, Newark, DE, USA
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19
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Smith CM, Hayamizu TF, Finger JH, Bello SM, McCright IJ, Xu J, Baldarelli RM, Beal JS, Campbell J, Corbani LE, Frost PJ, Lewis JR, Giannatto SC, Miers D, Shaw DR, Kadin JA, Richardson JE, Smith CL, Ringwald M. The mouse Gene Expression Database (GXD): 2019 update. Nucleic Acids Res 2020; 47:D774-D779. [PMID: 30335138 PMCID: PMC6324054 DOI: 10.1093/nar/gky922] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 10/04/2018] [Indexed: 11/13/2022] Open
Abstract
The mouse Gene Expression Database (GXD) is an extensive, well-curated community resource freely available at www.informatics.jax.org/expression.shtml. Covering all developmental stages, GXD includes data from RNA in situ hybridization, immunohistochemistry, RT-PCR, northern blot and western blot experiments in wild-type and mutant mice. GXD's gene expression information is integrated with the other data in Mouse Genome Informatics and interconnected with other databases, placing these data in the larger biological and biomedical context. Since the last report, the ability of GXD to provide insights into the molecular mechanisms of development and disease has been greatly enhanced by the addition of new data and by the implementation of new web features. These include: improvements to the Differential Gene Expression Data Search, facilitating searches for genes that have been shown to be exclusively expressed in a specified structure and/or developmental stage; an enhanced anatomy browser that now provides access to expression data and phenotype data for a given anatomical structure; direct access to the wild-type gene expression data for the tissues affected in a specific mutant; and a comparison matrix that juxtaposes tissues where a gene is normally expressed against tissues, where mutations in that gene cause abnormalities.
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Affiliation(s)
| | - Terry F Hayamizu
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | | | - Susan M Bello
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | | | - Jingxia Xu
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | | | - Jonathan S Beal
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Jeffrey Campbell
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Lori E Corbani
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Pete J Frost
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Jill R Lewis
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | | | - Dave Miers
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - David R Shaw
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - James A Kadin
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | | | - Cynthia L Smith
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Martin Ringwald
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
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20
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Bult CJ, Blake JA, Smith CL, Kadin JA, Richardson JE. Mouse Genome Database (MGD) 2019. Nucleic Acids Res 2020; 47:D801-D806. [PMID: 30407599 PMCID: PMC6323923 DOI: 10.1093/nar/gky1056] [Citation(s) in RCA: 497] [Impact Index Per Article: 99.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 10/30/2018] [Indexed: 01/19/2023] Open
Abstract
The Mouse Genome Database (MGD; http://www.informatics.jax.org) is the community model organism genetic and genome resource for the laboratory mouse. MGD is the authoritative source for biological reference data sets related to mouse genes, gene functions, phenotypes, and mouse models of human disease. MGD is the primary outlet for official gene, allele and mouse strain nomenclature based on the guidelines set by the International Committee on Standardized Nomenclature for Mice. In this report we describe significant enhancements to MGD, including two new graphical user interfaces: (i) the Multi Genome Viewer for exploring the genomes of multiple mouse strains and (ii) the Phenotype-Gene Expression matrix which was developed in collaboration with the Gene Expression Database (GXD) and allows researchers to compare gene expression and phenotype annotations for mouse genes. Other recent improvements include enhanced efficiency of our literature curation processes and the incorporation of Transcriptional Start Site (TSS) annotations from RIKEN's FANTOM 5 initiative.
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Affiliation(s)
- Carol J Bult
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Judith A Blake
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Cynthia L Smith
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - James A Kadin
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
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21
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Hsieh A, Morton SU, Willcox JAL, Gorham JM, Tai AC, Qi H, DePalma S, McKean D, Griffin E, Manheimer KB, Bernstein D, Kim RW, Newburger JW, Porter GA, Srivastava D, Tristani-Firouzi M, Brueckner M, Lifton RP, Goldmuntz E, Gelb BD, Chung WK, Seidman CE, Seidman JG, Shen Y. EM-mosaic detects mosaic point mutations that contribute to congenital heart disease. Genome Med 2020; 12:42. [PMID: 32349777 PMCID: PMC7189690 DOI: 10.1186/s13073-020-00738-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 04/09/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined. METHODS We developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available. RESULTS EM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction. CONCLUSIONS We estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses.
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Affiliation(s)
- Alexander Hsieh
- Columbia University Medical Center, 1130 St Nicholas Ave, New York, NY 10032 USA
| | - Sarah U. Morton
- Boston Children’s Hospital, Boston, MA USA
- Harvard Medical School, Boston, MA USA
| | | | | | | | - Hongjian Qi
- Columbia University Medical Center, 1130 St Nicholas Ave, New York, NY 10032 USA
| | | | | | - Emily Griffin
- Columbia University Medical Center, 1130 St Nicholas Ave, New York, NY 10032 USA
| | | | | | | | | | | | - Deepak Srivastava
- Gladstone Institutes and University of California San Francisco, San Francisco, CA USA
| | | | | | | | | | - Bruce D. Gelb
- Icahn School of Medicine at Mount Sinai, New York, NY USA
| | - Wendy K. Chung
- Columbia University Medical Center, 1130 St Nicholas Ave, New York, NY 10032 USA
| | - Christine E. Seidman
- Harvard Medical School, Boston, MA USA
- Brigham and Women’s Hospital, Boston, MA USA
- Howard Hughes Medical Institute, Harvard University, Boston, MA USA
| | | | - Yufeng Shen
- Columbia University Medical Center, 1130 St Nicholas Ave, New York, NY 10032 USA
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22
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Wade EM, Halliday BJ, Jenkins ZA, O'Neill AC, Robertson SP. The X‐linked filaminopathies: Synergistic insights from clinical and molecular analysis. Hum Mutat 2020; 41:865-883. [DOI: 10.1002/humu.24002] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/30/2020] [Accepted: 02/24/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Emma M. Wade
- Department of Women's and Children's Health, Dunedin School of MedicineUniversity of Otago Dunedin New Zealand
| | - Benjamin J. Halliday
- Department of Women's and Children's Health, Dunedin School of MedicineUniversity of Otago Dunedin New Zealand
| | - Zandra A. Jenkins
- Department of Women's and Children's Health, Dunedin School of MedicineUniversity of Otago Dunedin New Zealand
| | - Adam C. O'Neill
- Department of Women's and Children's Health, Dunedin School of MedicineUniversity of Otago Dunedin New Zealand
| | - Stephen P. Robertson
- Department of Women's and Children's Health, Dunedin School of MedicineUniversity of Otago Dunedin New Zealand
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23
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Singh AN, Gasman B. Disentangling the genetics of sarcopenia: prioritization of NUDT3 and KLF5 as genes for lean mass & HLA-DQB1-AS1 for hand grip strength with the associated enhancing SNPs & a scoring system. BMC MEDICAL GENETICS 2020; 21:40. [PMID: 32093658 PMCID: PMC7041234 DOI: 10.1186/s12881-020-0977-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 02/18/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Sarcopenia is a skeletal muscle disease of clinical importance that occurs commonly in old age and in various disease sub-categories. Widening the scope of knowledge of the genetics of muscle mass and strength is important because it may allow to identify patients with an increased risk to develop a specific musculoskeletal disease or condition such as sarcopenia based on genetic markers. METHODS We used bioinformatics tools to identify gene loci responsible for regulating muscle strength and lean mass, which can then be a target for downstream lab experimentation validation. Single nuclear polymorphisms (SNPs) associated with various disease traits of muscles and specific genes were chosen according to their muscle phenotype association p-value, as traditionally done in Genome Wide Association Studies, GWAS. We've developed and applied a combination of expression quantitative trait loci (eQTLs) and GWAS summary information, to prioritize causative SNP and point out the unique genes associated in the tissues of interest (muscle). RESULTS We found NUDT3 and KLF5 for lean mass and HLA-DQB1-AS1 for hand grip strength as candidate genes to target for these phenotypes. The associated regulatory SNPs are rs464553, rs1028883 and rs3129753 respectively. CONCLUSION Transcriptome Wide Association Studies, TWAS, approaches of combining GWAS and eQTL summary statistics proved helpful in statistically prioritizing genes and their associated SNPs for the disease phenotype of study, in this case, Sarcopenia. Potentially regulatory SNPs associated with these genes, and the genes further prioritized by a scoring system, can be then wet lab verified, depending on the phenotype it is hypothesized to affect.
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Affiliation(s)
- Abhishek Narain Singh
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
- Faculty of Medicine, Bar Ilan University, Safed, Israel
| | - Bili Gasman
- Faculty of Medicine, Bar Ilan University, Safed, Israel
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24
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Prajapati RS, Mitter R, Vezzaro A, Ish-Horowicz D. Greb1 is required for axial elongation and segmentation in vertebrate embryos. Biol Open 2020; 9:bio047290. [PMID: 31988092 PMCID: PMC7044451 DOI: 10.1242/bio.047290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/06/2020] [Indexed: 01/08/2023] Open
Abstract
During vertebrate embryonic development, the formation of axial structures is driven by a population of stem-like cells that reside in a region of the tailbud called the chordoneural hinge (CNH). We have compared the mouse CNH transcriptome with those of surrounding tissues and shown that the CNH and tailbud mesoderm are transcriptionally similar, and distinct from the presomitic mesoderm. Amongst CNH-enriched genes are several that are required for axial elongation, including Wnt3a, Cdx2, Brachyury/T and Fgf8, and androgen/oestrogen receptor nuclear signalling components such as Greb1 We show that the pattern and duration of tailbud Greb1 expression is conserved in mouse, zebrafish and chicken embryos, and that Greb1 is required for axial elongation and somitogenesis in zebrafish embryos. The axial truncation phenotype of Greb1 morphant embryos can be explained by much reduced expression of No tail (Ntl/Brachyury), which is required for axial progenitor maintenance. Posterior segmentation defects in the morphants (including misexpression of genes such as mespb, myoD and papC) appear to result, in part, from lost expression of the segmentation clock gene, her7.
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Affiliation(s)
| | - Richard Mitter
- Cancer Research UK Developmental Genetics Laboratory, CRUK London Research Institute
- Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK
| | - Annalisa Vezzaro
- Cancer Research UK Developmental Genetics Laboratory, CRUK London Research Institute
- Veyrier, 1255, Switzerland
| | - David Ish-Horowicz
- Cancer Research UK Developmental Genetics Laboratory, CRUK London Research Institute
- Cancer Research UK Developmental Genetics Laboratory, and University College London, UK
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25
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Roy J, Cheung E, Bhatti J, Muneem A, Lobo D. Curation and annotation of planarian gene expression patterns with segmented reference morphologies. Bioinformatics 2020; 36:2881-2887. [DOI: 10.1093/bioinformatics/btaa023] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 12/07/2019] [Accepted: 01/14/2020] [Indexed: 12/30/2022] Open
Abstract
Abstract
Motivation
Morphological and genetic spatial data from functional experiments based on genetic, surgical and pharmacological perturbations are being produced at an extraordinary pace in developmental and regenerative biology. However, our ability to extract knowledge from these large datasets are hindered due to the lack of formalization methods and tools able to unambiguously describe, centralize and interpret them. Formalizing spatial phenotypes and gene expression patterns is especially challenging in organisms with highly variable morphologies such as planarian worms, which due to their extraordinary regenerative capability can experimentally result in phenotypes with almost any combination of body regions or parts.
Results
Here, we present a computational methodology and mathematical formalism to encode and curate the morphological outcomes and gene expression patterns in planaria. Worm morphologies are encoded with mathematical graphs based on anatomical ontology terms to automatically generate reference morphologies. Gene expression patterns are registered to these standard reference morphologies, which can then be annotated automatically with anatomical ontology terms by analyzing the spatial expression patterns and their textual descriptions. This methodology enables the curation and annotation of complex experimental morphologies together with their gene expression patterns in a centralized standardized dataset, paving the way for the extraction of knowledge and reverse-engineering of the much sought-after mechanistic models in planaria and other regenerative organisms.
Availability and implementation
We implemented this methodology in a user-friendly graphical software tool, PlanGexQ, freely available together with the data in the manuscript at https://lobolab.umbc.edu/plangexq.
Supplementary information
Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Joy Roy
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
| | - Eric Cheung
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
| | - Junaid Bhatti
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
| | - Abraar Muneem
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
| | - Daniel Lobo
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
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26
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Tran TQ, Hsu YM, Huang YC, Chen CJ, Lin WD, Lin YJ, Liao WL, Lin WY, Yang JS, Sheu JC, Chen SY, Tsai FJ. Integrated analysis of gene modulation profile identifies pathogenic factors and pathways in the liver of diabetic mice. J Diabetes Metab Disord 2020; 18:471-485. [PMID: 31890673 DOI: 10.1007/s40200-019-00453-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 10/10/2019] [Indexed: 12/23/2022]
Abstract
Purpose Type-2 diabetes mellitus (T2D) is a metabolic disorder that can progress to a serious chronic disease and frequently develops in obese individuals in association with various pathogenic complications that shorten the lifespan of these patients. The liver is an important organ regulating lipid metabolism, which is damaged in both obesity and T2D; however, the specific pathways involved in these pathogenic effects remain unclear. Establishing a suitable animal model that effectively mimics the human biological condition is a critical factor to allow for precise identification of T2D-related genes. Methods The KK.Cg-Ay mouse strain is one such model that has offered insight into obesity-related T2D pathogenesis. To comprehensively assess the association between obesity and T2D, in the present study, we performed microarray analysis on liver tissue samples of KK.Cg-Ay and KK-α/α wild-type mice to examine differences in gene expression and methylation patterns and their related biological processes and pathways. Results We found that inflammation accompanied by abnormal lipid metabolism led to the spontaneous mechanism of obesity-induced diabetes, resulting in differential expression of some genes related to the terms of insulin resistance and glucose tolerance. Surprisingly, disruption of steroid biosynthesis strongly facilitated the diabetic pathogenesis. To support these findings, we highlighted some candidate genes and determined their relationships in biological networks of obesity-induced T2D. Conclusion These findings provide valuable reference data that can facilitate further detailed investigations to elucidate the pathogenic mechanism of obesity-induced diabetes in mice, which can be associated with the human condition to inform new prevention and treatment strategies.
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Affiliation(s)
- Thai Quoc Tran
- 1Graduate Institute of Biomedical Science, China Medical University, Taichung, 404 Taiwan
| | - Yuan-Man Hsu
- 2Department of Biological Science and Technology, China Medical University, Taichung, 404 Taiwan
| | - Yu-Chuen Huang
- 3Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung, 404 Taiwan.,4School of Chinese Medicine, China Medical University, Taichung, 404 Taiwan
| | - Chao-Jung Chen
- 3Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung, 404 Taiwan.,4School of Chinese Medicine, China Medical University, Taichung, 404 Taiwan
| | - Wei-De Lin
- 3Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung, 404 Taiwan.,4School of Chinese Medicine, China Medical University, Taichung, 404 Taiwan
| | - Ying-Ju Lin
- 3Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung, 404 Taiwan.,4School of Chinese Medicine, China Medical University, Taichung, 404 Taiwan
| | - Wen-Ling Liao
- 3Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung, 404 Taiwan.,4School of Chinese Medicine, China Medical University, Taichung, 404 Taiwan
| | - Wei-Yong Lin
- 3Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung, 404 Taiwan.,4School of Chinese Medicine, China Medical University, Taichung, 404 Taiwan
| | - Jai-Sing Yang
- 3Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung, 404 Taiwan
| | - Jinn-Chyuan Sheu
- 5Institute of Biomedical Science, National Sun Yat-sen University, Kaohsiung, 80424 Taiwan
| | - Shih-Yin Chen
- 3Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung, 404 Taiwan.,4School of Chinese Medicine, China Medical University, Taichung, 404 Taiwan
| | - Fuu-Jen Tsai
- 3Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung, 404 Taiwan.,4School of Chinese Medicine, China Medical University, Taichung, 404 Taiwan.,6Department of Medical Genetics, China Medical University Hospital, Taichung, 404 Taiwan
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27
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Amrom D, Poduri A, Goldman JS, Dan B, Deconinck N, Pichon B, Nadaf J, Andermann F, Andermann E, Walsh CA, Dobyns WB. Duplication 2p16 is associated with perisylvian polymicrogyria. Am J Med Genet A 2019; 179:2343-2356. [PMID: 31660690 DOI: 10.1002/ajmg.a.61342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 07/01/2019] [Accepted: 08/12/2019] [Indexed: 11/07/2022]
Abstract
Polymicrogyria (PMG) is a heterogeneous brain malformation that may result from prenatal vascular disruption or infection, or from numerous genetic causes that still remain difficult to identify. We identified three unrelated patients with polymicrogyria and duplications of chromosome 2p, defined the smallest region of overlap, and performed gene pathway analysis using Cytoscape. The smallest region of overlap in all three children involved 2p16.1-p16.3. All three children have bilateral perisylvian polymicrogyria (BPP), intrauterine and postnatal growth deficiency, similar dysmorphic features, and poor feeding. Two of the three children had documented intellectual disability. Gene pathway analysis suggested a number of developmentally relevant genes and gene clusters that were over-represented in the critical region. We narrowed a rare locus for polymicrogyria to a region of 2p16.1-p16.3 that contains 33-34 genes, 23 of which are expressed in cerebral cortex during human fetal development. Using pathway analysis, we showed that several of the duplicated genes contribute to neurodevelopmental pathways including morphogen, cytokine, hormonal and growth factor signaling, regulation of cell cycle progression, cell morphogenesis, axonal guidance, and neuronal migration. These findings strengthen the evidence for a novel locus associated with polymicrogyria on 2p16.1-p16.3, and comprise the first step in defining the underlying genetic etiology.
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Affiliation(s)
- Dina Amrom
- Neurogenetics Unit, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.,Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada.,Department of Neurology, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Annapurna Poduri
- Division of Epilepsy & Clinical Neurophysiology, Children's Hospital, Boston, Massachusetts.,Department of Neurology, Children's Hospital, Boston, Massachusetts
| | - Jennifer S Goldman
- Ludmer Centre for Neuroinformatics and Mental Health and the Department of Biomedical Engineering, McGill Centre for Integrative Neuroscience, McGill University, Montreal, Quebec, Canada
| | | | | | - Bruno Pichon
- Department of Medical Genetics, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Javad Nadaf
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada.,Genome Quebec Innovation Center, McGill University, Montreal, Quebec, Canada
| | - Frederick Andermann
- Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada.,Epilepsy Research Group, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.,Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | - Eva Andermann
- Neurogenetics Unit, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.,Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada.,Department of Human Genetics, McGill University, Montreal, Quebec, Canada.,Epilepsy Research Group, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada
| | - Christopher A Walsh
- Department of Neurology, Children's Hospital, Boston, Massachusetts.,Division of Genetics and Manton Center for Orphan Disease Research, Children's Hospital, Boston, Massachusetts.,Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts
| | - William B Dobyns
- Department of Pediatrics (Genetics) and Neurology, University of Washington, and Seattle Children's Research Institute, Seattle, Washington
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28
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Feigin CY, Newton AH, Pask AJ. Widespread cis-regulatory convergence between the extinct Tasmanian tiger and gray wolf. Genome Res 2019; 29:1648-1658. [PMID: 31533979 PMCID: PMC6771401 DOI: 10.1101/gr.244251.118] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 08/19/2019] [Indexed: 12/18/2022]
Abstract
The extinct marsupial Tasmanian tiger, or thylacine, and the eutherian gray wolf are among the most widely recognized examples of convergent evolution in mammals. Despite being distantly related, these large predators independently evolved extremely similar craniofacial morphologies, and evidence suggests that they filled similar ecological niches. Previous analyses revealed little evidence of adaptive convergence between their protein-coding genes. Thus, the genetic basis of their convergence is still unclear. Here, we identified candidate craniofacial cis-regulatory elements across vertebrates and compared their evolutionary rates in the thylacine and wolf, revealing abundant signatures of convergent positive selection. Craniofacial thylacine-wolf accelerated regions were enriched near genes involved in TGF beta (TGFB) and BMP signaling, both of which are key morphological signaling pathways with critical roles in establishing the identities and boundaries between craniofacial tissues. Similarly, enhancers of genes involved in craniofacial nerve development showed convergent selection and involvement in these pathways. Taken together, these results suggest that adaptation in cis-regulators of TGF beta and BMP signaling may provide a mechanism to explain the coevolution of developmentally and functionally integrated craniofacial structures in these species. We also found that despite major structural differences in marsupial and eutherian brains, accelerated regions in both species were common near genes with roles in brain development. Our findings support the hypothesis that, relative to protein-coding genes, positive selection on cis-regulatory elements is likely to be an essential driver of adaptive convergent evolution and may underpin thylacine-wolf phenotypic similarities.
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Affiliation(s)
- Charles Y Feigin
- School of BioSciences, The University of Melbourne, Parkville, Victoria 3010, Australia.,Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
| | - Axel H Newton
- School of BioSciences, The University of Melbourne, Parkville, Victoria 3010, Australia.,Museums Victoria, Melbourne, Victoria 3053, Australia
| | - Andrew J Pask
- School of BioSciences, The University of Melbourne, Parkville, Victoria 3010, Australia.,Museums Victoria, Melbourne, Victoria 3053, Australia
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29
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Nfonsam LE, Jandova J, Jecius HC, Omesiete PN, Nfonsam VN. SFRP4 expression correlates with epithelial mesenchymal transition-linked genes and poor overall survival in colon cancer patients. World J Gastrointest Oncol 2019; 11:589-598. [PMID: 31435461 PMCID: PMC6700031 DOI: 10.4251/wjgo.v11.i8.589] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 04/02/2019] [Accepted: 05/23/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Colon cancer is among the most commonly diagnosed cancers in the United States with an estimated 97220 new cases expected by the end of 2018. It affects 1.2 million people around the world and is responsible for about 0.6 million deaths every year. Despite decline in overall incidence and mortality over the past 30 years, there continues to be an alarming rise in early-onset colon cancer cases (< 50 years). Patients are often diagnosed at late stages of the disease and tend to have poor survival. We previously showed that the WNT “gatekeeper” gene, secreted frizzled-related protein 4 (SFRP4), is over-expressed in early-onset colon cancer. SFRP4 is speculated to play an essential role in cancer by inhibiting the epithelial mesenchymal transition (EMT).
AIM To investigate the correlation between SFRP4 expression and EMT-linked genes in colon cancer and how it affects patient survival.
METHODS SFRP4 expression relative to that of EMT-linked genes and survival analysis were performed using the University of California Santa Cruz Cancer Browser interface.
RESULTS SFRP4 was found to be co-expressed with the EMT-linked markers CDH2, FN1, VIM, TWIST1, TWIST2, SNAI1, SNAI2, ZEB1, ZEB2, POSTN, MMP2, MMP7, MMP9, and COL1A1. SFRP4 expression negatively correlated with the EMT-linked suppressors CLDN4, CLDN7, TJP3, MUC1, and CDH1. The expression of SFRP4 and the EMT-linked markers was higher in mesenchymal-like samples compared to epithelial-like samples which potentially implicates SFRP4-EMT mechanism in colon cancer. Additionally, patients overexpressing SFRP4 presented with poor overall survival (P = 0.0293).
CONCLUSION Considering the implication of SFRP4 in early-onset colon cancer, particularly in the context of EMT, tumor metastasis, and invasion, and the effect of increased expression on colon cancer patient survival, SFRP4 might be a potential biomarker for early-onset colon cancer that could be targeted for diagnosis and/or disease therapy.
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Affiliation(s)
- Landry E Nfonsam
- Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada
| | - Jana Jandova
- Department of Surgery, University of Arizona, Tucson, AZ 85724, United States
| | - Hunter C Jecius
- Department of Surgery, University of Arizona, Tucson, AZ 85724, United States
| | - Pamela N Omesiete
- Department of Surgery, University of Arizona, Tucson, AZ 85724, United States
| | - Valentine N Nfonsam
- Department of Surgery, University of Arizona, Tucson, AZ 85724, United States
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30
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Smith CL, Blake JA, Kadin JA, Richardson JE, Bult CJ. Mouse Genome Database (MGD)-2018: knowledgebase for the laboratory mouse. Nucleic Acids Res 2019; 46:D836-D842. [PMID: 29092072 PMCID: PMC5753350 DOI: 10.1093/nar/gkx1006] [Citation(s) in RCA: 163] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 10/19/2017] [Indexed: 12/23/2022] Open
Abstract
The Mouse Genome Database (MGD; http://www.informatics.jax.org) is the key community mouse database which supports basic, translational and computational research by providing integrated data on the genetics, genomics, and biology of the laboratory mouse. MGD serves as the source for biological reference data sets related to mouse genes, gene functions, phenotypes and disease models with an increasing emphasis on the association of these data to human biology and disease. We report here on recent enhancements to this resource, including improved access to mouse disease model and human phenotype data and enhanced relationships of mouse models to human disease.
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Affiliation(s)
- Cynthia L Smith
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Judith A Blake
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - James A Kadin
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | | | - Carol J Bult
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
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Recla JM, Bubier JA, Gatti DM, Ryan JL, Long KH, Robledo RF, Glidden NC, Hou G, Churchill GA, Maser RS, Zhang ZW, Young EE, Chesler EJ, Bult CJ. Genetic mapping in Diversity Outbred mice identifies a Trpa1 variant influencing late-phase formalin response. Pain 2019; 160:1740-1753. [PMID: 31335644 PMCID: PMC6668363 DOI: 10.1097/j.pain.0000000000001571] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Identification of genetic variants that influence susceptibility to pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with persistent pain, we measured late-phase response to formalin injection in 275 male and female Diversity Outbred mice genotyped for over 70,000 single nucleotide polymorphisms. One quantitative trait locus reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus, Nociq4 (nociceptive sensitivity quantitative trait locus 4; MGI: 5661503), harbors the well-known pain gene Trpa1 (transient receptor potential cation channel, subfamily A, member 1). Trpa1 is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of Diversity Outbred founder strain allele effects revealed a significant effect of the CAST/EiJ allele at Trpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the 7 other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants in Trpa1 by assessing channel conductance, TRPA1-TRPV1 interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained by Trpa1 isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity.
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Affiliation(s)
- Jill M. Recla
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
- IGERT Program in Functional Genomics, Graduate School of Biomedical Sciences and Engineering, The University of Maine, Orono, ME 04469, USA
| | - Jason A. Bubier
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Daniel M. Gatti
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Jennifer L. Ryan
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Katie H. Long
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | | | - Nicole C. Glidden
- Department of Genetics and Genome Sciences, UCONN Health, 400 Farmington Avenue, Farmington, CT 06030-6403, USA
| | - Guoqiang Hou
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | | | - Richard S. Maser
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Zhong-wei Zhang
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Erin E. Young
- Department of Genetics and Genome Sciences, UCONN Health, 400 Farmington Avenue, Farmington, CT 06030-6403, USA
- School of Nursing, University of Connecticut, 231 Glenbrook Rd, Unit 4026, Storrs, CT 06269-4026, USA
- Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269-4026, USA
| | | | - Carol J. Bult
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
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32
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Sheehan MJ, Campbell P, Miller CH. Evolutionary patterns of major urinary protein scent signals in house mice and relatives. Mol Ecol 2019; 28:3587-3601. [DOI: 10.1111/mec.15155] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 06/10/2019] [Accepted: 06/12/2019] [Indexed: 01/04/2023]
Affiliation(s)
| | - Polly Campbell
- Evolution, Ecology and Organismal Biology University of California – Riverside Riverside CA USA
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33
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Vijayakumar S, Conway M, Lió P, Angione C. Seeing the wood for the trees: a forest of methods for optimization and omic-network integration in metabolic modelling. Brief Bioinform 2019; 19:1218-1235. [PMID: 28575143 DOI: 10.1093/bib/bbx053] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Indexed: 11/13/2022] Open
Abstract
Metabolic modelling has entered a mature phase with dozens of methods and software implementations available to the practitioner and the theoretician. It is not easy for a modeller to be able to see the wood (or the forest) for the trees. Driven by this analogy, we here present a 'forest' of principal methods used for constraint-based modelling in systems biology. This provides a tree-based view of methods available to prospective modellers, also available in interactive version at http://modellingmetabolism.net, where it will be kept updated with new methods after the publication of the present manuscript. Our updated classification of existing methods and tools highlights the most promising in the different branches, with the aim to develop a vision of how existing methods could hybridize and become more complex. We then provide the first hands-on tutorial for multi-objective optimization of metabolic models in R. We finally discuss the implementation of multi-view machine learning approaches in poly-omic integration. Throughout this work, we demonstrate the optimization of trade-offs between multiple metabolic objectives, with a focus on omic data integration through machine learning. We anticipate that the combination of a survey, a perspective on multi-view machine learning and a step-by-step R tutorial should be of interest for both the beginner and the advanced user.
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Affiliation(s)
| | - Max Conway
- Computer Laboratory, University of Cambridge, UK
| | - Pietro Lió
- Computer Laboratory, University of Cambridge, UK
| | - Claudio Angione
- Department of Computer Science and Information Systems, Teesside University, UK
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34
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Berger MJ, Wenger AM, Guturu H, Bejerano G. Independent erosion of conserved transcription factor binding sites points to shared hindlimb, vision and external testes loss in different mammals. Nucleic Acids Res 2019; 46:9299-9308. [PMID: 30137416 PMCID: PMC6182171 DOI: 10.1093/nar/gky741] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 08/21/2018] [Indexed: 02/05/2023] Open
Abstract
Genetic variation in cis-regulatory elements is thought to be a major driving force in morphological and physiological changes. However, identifying transcription factor binding events that code for complex traits remains a challenge, motivating novel means of detecting putatively important binding events. Using a curated set of 1154 high-quality transcription factor motifs, we demonstrate that independently eroded binding sites are enriched for independently lost traits in three distinct pairs of placental mammals. We show that these independently eroded events pinpoint the loss of hindlimbs in dolphin and manatee, degradation of vision in naked mole-rat and star-nosed mole, and the loss of external testes in white rhinoceros and Weddell seal. We additionally show that our method may also be utilized with more than two species. Our study exhibits a novel methodology to detect cis-regulatory mutations which help explain a portion of the molecular mechanism underlying complex trait formation and loss.
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Affiliation(s)
- Mark J Berger
- Department of Computer Science, Stanford University, Stanford, CA 94305-5329, USA
| | - Aaron M Wenger
- Department of Computer Science, Stanford University, Stanford, CA 94305-5329, USA
| | - Harendra Guturu
- Department of Electrical Engineering, Stanford University, Stanford, CA 94305-5008, USA
| | - Gill Bejerano
- Department of Computer Science, Stanford University, Stanford, CA 94305-5329, USA.,Department of Developmental Biology, Stanford University, Stanford, CA 94305-5329, USA.,Department of Pediatrics, Stanford University, Stanford, CA 94305-5208, USA.,Department of Biomedical Data Science, Stanford University, Stanford, CA 94305-5464, USA
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35
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Castro JPL, Yancoskie MN, Marchini M, Belohlavy S, Hiramatsu L, Kučka M, Beluch WH, Naumann R, Skuplik I, Cobb J, Barton NH, Rolian C, Chan YF. An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice. eLife 2019; 8:e42014. [PMID: 31169497 PMCID: PMC6606024 DOI: 10.7554/elife.42014] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 05/19/2019] [Indexed: 12/30/2022] Open
Abstract
Evolutionary studies are often limited by missing data that are critical to understanding the history of selection. Selection experiments, which reproduce rapid evolution under controlled conditions, are excellent tools to study how genomes evolve under selection. Here we present a genomic dissection of the Longshanks selection experiment, in which mice were selectively bred over 20 generations for longer tibiae relative to body mass, resulting in 13% longer tibiae in two replicates. We synthesized evolutionary theory, genome sequences and molecular genetics to understand the selection response and found that it involved both polygenic adaptation and discrete loci of major effect, with the strongest loci tending to be selected in parallel between replicates. We show that selection may favor de-repression of bone growth through inactivating two limb enhancers of an inhibitor, Nkx3-2. Our integrative genomic analyses thus show that it is possible to connect individual base-pair changes to the overall selection response.
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Affiliation(s)
- João PL Castro
- Friedrich Miescher Laboratory of the Max Planck SocietyTübingenGermany
| | | | | | | | - Layla Hiramatsu
- Friedrich Miescher Laboratory of the Max Planck SocietyTübingenGermany
| | - Marek Kučka
- Friedrich Miescher Laboratory of the Max Planck SocietyTübingenGermany
| | - William H Beluch
- Friedrich Miescher Laboratory of the Max Planck SocietyTübingenGermany
| | - Ronald Naumann
- Max Planck Institute for Molecular Cell Biology and GeneticsDresdenGermany
| | | | | | - Nicholas H Barton
- Institute of Science and Technology (IST) AustriaKlosterneuburgAustria
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36
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Barón-Mendoza I, Del Moral-Sánchez I, Martínez-Marcial M, García O, Garzón-Cortés D, González-Arenas A. Dendritic complexity in prefrontal cortex and hippocampus of the autistic-like mice C58/J. Neurosci Lett 2019; 703:149-155. [DOI: 10.1016/j.neulet.2019.03.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 03/11/2019] [Accepted: 03/12/2019] [Indexed: 11/17/2022]
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37
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Kimura K, Inaba Y, Watanabe H, Matsukawa T, Matsumoto M, Inoue H. Nicotinic alpha-7 acetylcholine receptor deficiency exacerbates hepatic inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis. J Diabetes Investig 2019; 10:659-666. [PMID: 30369082 PMCID: PMC6497582 DOI: 10.1111/jdi.12964] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 10/04/2018] [Accepted: 10/25/2018] [Indexed: 12/15/2022] Open
Abstract
AIMS/INTRODUCTION Non-alcoholic steatohepatitis (NASH), which occurs in association with insulin resistance and hepatic fat accumulation, is characterized by chronic liver injury and fibrosis. NASH onset and progression is closely related to hepatic inflammation, which is partly regulated by the vagus nerve through the α7 nicotinic acetylcholine receptor (α7nAchR). Hepatic α7nAchR action is impeded in obesity and insulin resistance. In the present study, using α7nAchR knockout (α7KO) mice, we elucidated the effect of α7nAchR deficiency on NASH-related inflammation and fibrosis. MATERIALS AND METHODS α7KO mice were fed an atherogenic high-fat diet (AD) for 32 weeks or methionine/choline-deficient diet (MCD) for 6 weeks, both of which induce NASH. Mice were then examined for the degree of NASH-related inflammation and fibrosis by hepatic gene expression analysis and Sirius red histological staining. RESULTS Hepatic triglyceride accumulation and elevated plasma transaminase levels were observed in both AD and MCD mice, but the plasma transaminase level increase was higher in α7KO mice than in control mice. α7KO mice fed an AD showed significant upregulation of the Col1a1 gene encoding alpha-1 type I collagen, which is involved in liver fibrosis, and the Ccl2 gene encoding C-C motif chemokine ligand 2, a pro-inflammatory chemokine; α7KO mice fed an MCD had significant upregulation of the Col1a1 gene and the Tnf gene, an inflammatory cytokine. Histological analysis showed that AD and MCD exacerbated liver fibrosis in α7KO mice. CONCLUSIONS The results of this study suggest that α7nAchR deficiency exacerbates hepatic inflammation and fibrosis in a diet-induced mouse model of NASH.
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Affiliation(s)
- Kumi Kimura
- Metabolism and Nutrition Research UnitInstitute for Frontier Science InitiativeKanazawa UniversityKanazawaJapan
| | - Yuka Inaba
- Metabolism and Nutrition Research UnitInstitute for Frontier Science InitiativeKanazawa UniversityKanazawaJapan
| | - Hitoshi Watanabe
- Metabolism and Nutrition Research UnitInstitute for Frontier Science InitiativeKanazawa UniversityKanazawaJapan
| | - Toshiya Matsukawa
- Department of Molecular Metabolic RegulationDiabetes Research CenterResearch InstituteNational Center for Global Health and MedicineTokyoJapan
| | - Michihiro Matsumoto
- Department of Molecular Metabolic RegulationDiabetes Research CenterResearch InstituteNational Center for Global Health and MedicineTokyoJapan
| | - Hiroshi Inoue
- Metabolism and Nutrition Research UnitInstitute for Frontier Science InitiativeKanazawa UniversityKanazawaJapan
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38
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Abstract
The primate cerebral cortex displays a hierarchy that extends from primary sensorimotor to association areas, supporting increasingly integrated function underpinned by a gradient of heterogeneity in the brain's microcircuits. The extent to which these hierarchical gradients are unique to primate or may reflect a conserved mammalian principle of brain organization remains unknown. Here we report the topographic similarity of large-scale gradients in cytoarchitecture, gene expression, interneuron cell densities, and long-range axonal connectivity, which vary from primary sensory to prefrontal areas of mouse cortex, highlighting an underappreciated spatial dimension of mouse cortical specialization. Using the T1-weighted:T2-weighted (T1w:T2w) magnetic resonance imaging map as a common spatial reference for comparison across species, we report interspecies agreement in a range of large-scale cortical gradients, including a significant correspondence between gene transcriptional maps in mouse cortex with their human orthologs in human cortex, as well as notable interspecies differences. Our results support the view of systematic structural variation across cortical areas as a core organizational principle that may underlie hierarchical specialization in mammalian brains.
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Affiliation(s)
- Ben D Fulcher
- School of Physics, Sydney University, Sydney, NSW 2006, Australia;
| | - John D Murray
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511
| | - Valerio Zerbi
- Neural Control of Movement Laboratory, Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich, 8057 Zürich, Switzerland
| | - Xiao-Jing Wang
- Center for Neural Science, New York University, New York, NY 10003;
- Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai 201210, China
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39
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Dantoft W, Robertson KA, Watkins WJ, Strobl B, Ghazal P. Metabolic Regulators Nampt and Sirt6 Serially Participate in the Macrophage Interferon Antiviral Cascade. Front Microbiol 2019; 10:355. [PMID: 30886604 PMCID: PMC6409323 DOI: 10.3389/fmicb.2019.00355] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 02/11/2019] [Indexed: 11/13/2022] Open
Abstract
Molecular determinants underlying interferon (IFN)-macrophage biology can help delineate enzyme systems, pathways and mechanisms for enabling host-directed therapeutic approaches against infection. Notably, while the IFN antiviral response is known to be directly coupled to mevalonate-sterol biosynthesis, mechanistic insight for providing host pathway-therapeutic targets remain incomplete. Here, we show that Nampt and Sirt6 are coordinately regulated upon immune activation of macrophages and contribute to the IFN-sterol antiviral response. In silico analysis of the Nampt and Sirt6 promoter regions identified multiple core immune gene-regulatory transcription factor sites, including Stat1, implicating a molecular link to IFN control. Experimentally, we show using a range of genetically IFN-defective macrophages that the expression of Nampt is stringently regulated by the Jak/Stat-pathway while Sirt6 activation is temporally displaced in a partial IFN-dependent manner. We further show that pharmacological inhibition of Nampt and small interfering RNA (siRNA)-mediated inhibition of Nampt and Sirt6 promotes viral growth of cytomegalovirus in both fibroblasts and macrophages. Our results support the notion of pharmacologically exploiting immune regulated enzyme systems of macrophages for use as an adjuvant-based therapy for augmenting host protective pathway responses to infection.
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Affiliation(s)
- Widad Dantoft
- Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Kevin A Robertson
- Division of Infection and Pathway Medicine, School of Biomedical Sciences, The University of Edinburgh, Edinburgh, United Kingdom
| | - W John Watkins
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Birgit Strobl
- Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Peter Ghazal
- Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom.,Division of Infection and Pathway Medicine, School of Biomedical Sciences, The University of Edinburgh, Edinburgh, United Kingdom
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40
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Wei Y, Xiong ZJ, Li J, Zou C, Cairo CW, Klassen JS, Privé GG. Crystal structures of human lysosomal EPDR1 reveal homology with the superfamily of bacterial lipoprotein transporters. Commun Biol 2019; 2:52. [PMID: 30729188 PMCID: PMC6363788 DOI: 10.1038/s42003-018-0262-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 12/11/2018] [Indexed: 01/01/2023] Open
Abstract
EPDR1, a member of the ependymin-related protein family, is a relatively uncharacterized protein found in the lysosomes and secretomes of most vertebrates. Despite having roles in human disease and health, the molecular functions of EPDR1 remain unknown. Here, we present crystal structures of human EPDR1 and reveal that the protein adopts a fold previously seen only in bacterial proteins related to the LolA lipoprotein transporter. EPDR1 forms a homodimer with an overall shape resembling a half-shell with two non-overlapping hydrophobic grooves on the flat side of the hemisphere. EPDR1 can interact with membranes that contain negatively charged lipids, including BMP and GM1, and we suggest that EPDR1 may function as a lysosomal activator protein or a lipid transporter. A phylogenetic analysis reveals that the fold is more widely distributed than previously suspected, with representatives identified in all branches of cellular life.
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Affiliation(s)
- Yong Wei
- Princess Margaret Cancer Centre, Toronto, M5G 1L7 ON Canada
| | - Zi Jian Xiong
- Department of Biochemistry, University of Toronto, Toronto, M5S 1A8 ON Canada
| | - Jun Li
- Alberta Glycomics Centre and Department of Chemistry, University of Alberta, Edmonton, T6G 2G2 AB Canada
| | - Chunxia Zou
- Alberta Glycomics Centre and Department of Chemistry, University of Alberta, Edmonton, T6G 2G2 AB Canada
| | - Christopher W. Cairo
- Alberta Glycomics Centre and Department of Chemistry, University of Alberta, Edmonton, T6G 2G2 AB Canada
| | - John S. Klassen
- Alberta Glycomics Centre and Department of Chemistry, University of Alberta, Edmonton, T6G 2G2 AB Canada
| | - Gilbert G. Privé
- Princess Margaret Cancer Centre, Toronto, M5G 1L7 ON Canada
- Department of Biochemistry, University of Toronto, Toronto, M5S 1A8 ON Canada
- Department of Medical Biophysics, University of Toronto, Toronto, M5G 1L7 ON Canada
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41
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Jiang X, Ringwald M, Blake JA, Arighi C, Zhang G, Shatkay H. An effective biomedical document classification scheme in support of biocuration: addressing class imbalance. Database (Oxford) 2019; 2019:baz045. [PMID: 31032839 PMCID: PMC6482935 DOI: 10.1093/database/baz045] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 02/26/2019] [Accepted: 03/18/2019] [Indexed: 01/01/2023]
Abstract
Published literature is an important source of knowledge supporting biomedical research. Given the large and increasing number of publications, automated document classification plays an important role in biomedical research. Effective biomedical document classifiers are especially needed for bio-databases, in which the information stems from many thousands of biomedical publications that curators must read in detail and annotate. In addition, biomedical document classification often amounts to identifying a small subset of relevant publications within a much larger collection of available documents. As such, addressing class imbalance is essential to a practical classifier. We present here an effective classification scheme for automatically identifying papers among a large pool of biomedical publications that contain information relevant to a specific topic, which the curators are interested in annotating. The proposed scheme is based on a meta-classification framework using cluster-based under-sampling combined with named-entity recognition and statistical feature selection strategies. We examined the performance of our method over a large imbalanced data set that was originally manually curated by the Jackson Laboratory's Gene Expression Database (GXD). The set consists of more than 90 000 PubMed abstracts, of which about 13 000 documents are labeled as relevant to GXD while the others are not relevant. Our results, 0.72 precision, 0.80 recall and 0.75 f-measure, demonstrate that our proposed classification scheme effectively categorizes such a large data set in the face of data imbalance.
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Affiliation(s)
- Xiangying Jiang
- Department of Computer and Information Sciences, University of Delaware, Newark, DE, USA
| | | | - Judith A Blake
- The Jackson Laboratory, 600 Main St., Bar Harbor, ME, USA
| | - Cecilia Arighi
- Department of Computer and Information Sciences, University of Delaware, Newark, DE, USA
- Center of Bioinformatics and Computational Biology, Delaware Biotechnology Institute, Newark, DE, USA
| | - Gongbo Zhang
- Department of Computer and Information Sciences, University of Delaware, Newark, DE, USA
| | - Hagit Shatkay
- Department of Computer and Information Sciences, University of Delaware, Newark, DE, USA
- Center of Bioinformatics and Computational Biology, Delaware Biotechnology Institute, Newark, DE, USA
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42
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Towards a Central Role of ISL1 in the Bladder Exstrophy⁻Epispadias Complex (BEEC): Computational Characterization of Genetic Variants and Structural Modelling. Genes (Basel) 2018; 9:genes9120609. [PMID: 30563179 PMCID: PMC6315746 DOI: 10.3390/genes9120609] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 11/28/2018] [Indexed: 12/13/2022] Open
Abstract
Genetic factors play a critical role in the development of human diseases. Recently, several molecular genetic studies have provided multiple lines of evidence for a critical role of genetic factors in the expression of human bladder exstrophy-epispadias complex (BEEC). At this point, ISL1 (ISL LIM homeobox 1) has emerged as the major susceptibility gene for classic bladder exstrophy (CBE), in a multifactorial disease model. Here, GWAS (Genome wide association studies) discovery and replication studies, as well as the re-sequencing of ISL1, identified sequence variants (rs9291768, rs6874700, c.137C > G (p.Ala46Gly)) associated with CBE. Here, we aimed to determine the molecular and functional consequences of these sequence variants and estimate the dependence of ISL1 protein on other predicted candidates. We used: (i) computational analysis of conserved sequence motifs to perform an evolutionary conservation analysis, based on a Bayesian algorithm, and (ii) computational 3D structural modeling. Furthermore, we looked into long non-coding RNAs (lncRNAs) residing within the ISL1 region, aiming to predict their targets. Our analysis suggests that the ISL1 protein specific N-terminal LIM domain (which harbors the variant c.137C > G), limits its transcriptional ability, and might interfere with ISL1-estrogen receptor α interactions. In conclusion, our analysis provides further useful insights about the ISL1 gene, which is involved in the formation of the BEEC, and in the development of the urinary bladder.
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Chambers JM, Poureetezadi SJ, Addiego A, Lahne M, Wingert RA. ppargc1a controls nephron segmentation during zebrafish embryonic kidney ontogeny. eLife 2018; 7:40266. [PMID: 30475208 PMCID: PMC6279350 DOI: 10.7554/elife.40266] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 11/23/2018] [Indexed: 02/06/2023] Open
Abstract
Nephron segmentation involves a concert of genetic and molecular signals that are not fully understood. Through a chemical screen, we discovered that alteration of peroxisome proliferator-activated receptor (PPAR) signaling disrupts nephron segmentation in the zebrafish embryonic kidney (Poureetezadi et al., 2016). Here, we show that the PPAR co-activator ppargc1a directs renal progenitor fate. ppargc1a mutants form a small distal late (DL) segment and an expanded proximal straight tubule (PST) segment. ppargc1a promotes DL fate by regulating the transcription factor tbx2b, and restricts expression of the transcription factor sim1a to inhibit PST fate. Interestingly, sim1a restricts ppargc1a expression to promote the PST, and PST development is fully restored in ppargc1a/sim1a-deficient embryos, suggesting Ppargc1a and Sim1a counterbalance each other in an antagonistic fashion to delineate the PST segment boundary during nephrogenesis. Taken together, our data reveal new roles for Ppargc1a during development, which have implications for understanding renal birth defects.
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Affiliation(s)
- Joseph M Chambers
- Department of Biological Sciences, University of Notre Dame, Indiana, United States.,Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Indiana, United States.,Center for Zebrafish Research, University of Notre Dame, Indiana, United States
| | - Shahram Jevin Poureetezadi
- Department of Biological Sciences, University of Notre Dame, Indiana, United States.,Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Indiana, United States.,Center for Zebrafish Research, University of Notre Dame, Indiana, United States
| | - Amanda Addiego
- Department of Biological Sciences, University of Notre Dame, Indiana, United States.,Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Indiana, United States.,Center for Zebrafish Research, University of Notre Dame, Indiana, United States
| | - Manuela Lahne
- Department of Biological Sciences, University of Notre Dame, Indiana, United States.,Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Indiana, United States.,Center for Zebrafish Research, University of Notre Dame, Indiana, United States
| | - Rebecca A Wingert
- Department of Biological Sciences, University of Notre Dame, Indiana, United States.,Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Indiana, United States.,Center for Zebrafish Research, University of Notre Dame, Indiana, United States
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44
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Jeffries L, Olivieri JE, Ji W, Spencer-Manzon M, Bale A, Konstantino M, Lakhani SA. Two siblings with a novel nonsense variant provide further delineation of the spectrum of recessive KLHL7 diseases. Eur J Med Genet 2018; 62:103551. [PMID: 30300710 DOI: 10.1016/j.ejmg.2018.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 08/28/2018] [Accepted: 10/04/2018] [Indexed: 01/26/2023]
Abstract
Mutations in Kelch-like family member 7 (KLHL7) have recently been described as a cause of a constellation of clinical findings with descriptions of both a Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1)-like, as well as a Bohring-Opitz syndrome (BOS)-like presentation. Here we report two siblings of Guatelmalan descent with a novel homozygous nonsense mutation (p.Arg326*) in KLHL7. These children have multiple dysmorphic features and developmental delay. Interestingly, their clinical traits inconsistently overlap both the CS/CISS1-like and BOS-like phenotypes, and the siblings also have subtle differences from each other, suggesting that clinicians need to be aware of the degree of variability in the presentations of these patients. Still, there is enough in common between patients with recessive KLHL7 mutations to define a novel multisystem disease that features various neurodevelopmental, musculoskeletal, dysmorphic, and other unique components. This report adds to the clinical features and disease-associated variants of the newly-recognized spectrum of KLHL7 mutations, and offers a new description, PERCHING, for the resulting syndrome.
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Affiliation(s)
- Lauren Jeffries
- Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
| | - Jordan E Olivieri
- Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
| | - Weizhen Ji
- Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
| | | | - Allen Bale
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
| | - Monica Konstantino
- Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
| | - Saquib A Lakhani
- Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
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Howe DG, Blake JA, Bradford YM, Bult CJ, Calvi BR, Engel SR, Kadin JA, Kaufman TC, Kishore R, Laulederkind SJF, Lewis SE, Moxon SAT, Richardson JE, Smith C. Model organism data evolving in support of translational medicine. Lab Anim (NY) 2018; 47:277-289. [PMID: 30224793 PMCID: PMC6322546 DOI: 10.1038/s41684-018-0150-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 08/13/2018] [Indexed: 02/07/2023]
Abstract
Model organism databases (MODs) have been collecting and integrating biomedical research data for 30 years and were designed to meet specific needs of each model organism research community. The contributions of model organism research to understanding biological systems would be hard to overstate. Modern molecular biology methods and cost reductions in nucleotide sequencing have opened avenues for direct application of model organism research to elucidating mechanisms of human diseases. Thus, the mandate for model organism research and databases has now grown to include facilitating use of these data in translational applications. Challenges in meeting this opportunity include the distribution of research data across many databases and websites, a lack of data format standards for some data types, and sustainability of scale and cost for genomic database resources like MODs. The issues of widely distributed data and application of data standards are some of the challenges addressed by FAIR (Findable, Accessible, Interoperable, and Re-usable) data principles. The Alliance of Genome Resources is now moving to address these challenges by bringing together expertly curated research data from fly, mouse, rat, worm, yeast, zebrafish, and the Gene Ontology consortium. Centralized multi-species data access, integration, and format standardization will lower the data utilization barrier in comparative genomics and translational applications and will provide a framework in which sustainable scale and cost can be addressed. This article presents a brief historical perspective on how the Alliance model organisms are complementary and how they have already contributed to understanding the etiology of human diseases. In addition, we discuss four challenges for using data from MODs in translational applications and how the Alliance is working to address them, in part by applying FAIR data principles. Ultimately, combined data from these animal models are more powerful than the sum of the parts.
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Affiliation(s)
- Douglas G Howe
- The Institute of Neuroscience, University of Oregon, Eugene, OR, USA.
| | | | - Yvonne M Bradford
- The Institute of Neuroscience, University of Oregon, Eugene, OR, USA
| | | | - Brian R Calvi
- Department of Biology, Indiana University, Bloomington, IN, USA
| | - Stacia R Engel
- Department of Genetics, Stanford University, Palo Alto, CA, USA
| | | | | | - Ranjana Kishore
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Stanley J F Laulederkind
- Department of Biomedical Engineering, Medical College of Wisconsin and Marquette University, Milwaukee, WI, USA
| | - Suzanna E Lewis
- Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
| | - Sierra A T Moxon
- The Institute of Neuroscience, University of Oregon, Eugene, OR, USA
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Ziros PG, Habeos IG, Chartoumpekis DV, Ntalampyra E, Somm E, Renaud CO, Bongiovanni M, Trougakos IP, Yamamoto M, Kensler TW, Santisteban P, Carrasco N, Ris-Stalpers C, Amendola E, Liao XH, Rossich L, Thomasz L, Juvenal GJ, Refetoff S, Sykiotis GP. NFE2-Related Transcription Factor 2 Coordinates Antioxidant Defense with Thyroglobulin Production and Iodination in the Thyroid Gland. Thyroid 2018; 28:780-798. [PMID: 29742982 PMCID: PMC5994681 DOI: 10.1089/thy.2018.0018] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND The thyroid gland has a special relationship with oxidative stress. While generation of oxidative substances is part of normal iodide metabolism during thyroid hormone synthesis, the gland must also defend itself against excessive oxidation in order to maintain normal function. Antioxidant and detoxification enzymes aid thyroid cells to maintain homeostasis by ameliorating oxidative insults, including during exposure to excess iodide, but the factors that coordinate their expression with the cellular redox status are not known. The antioxidant response system comprising the ubiquitously expressed NFE2-related transcription factor 2 (Nrf2) and its redox-sensitive cytoplasmic inhibitor Kelch-like ECH-associated protein 1 (Keap1) defends tissues against oxidative stress, thereby protecting against pathologies that relate to DNA, protein, and/or lipid oxidative damage. Thus, it was hypothesized that Nrf2 should also have important roles in maintaining thyroid homeostasis. METHODS Ubiquitous and thyroid-specific male C57BL6J Nrf2 knockout (Nrf2-KO) mice were studied. Plasma and thyroids were harvested for evaluation of thyroid function tests by radioimmunoassays and of gene and protein expression by real-time polymerase chain reaction and immunoblotting, respectively. Nrf2-KO and Keap1-KO clones of the PCCL3 rat thyroid follicular cell line were generated using CRISPR/Cas9 technology and were used for gene and protein expression studies. Software-predicted Nrf2 binding sites on the thyroglobulin enhancer were validated by site-directed in vitro mutagenesis and chromatin immunoprecipitation. RESULTS The study shows that Nrf2 mediates antioxidant transcriptional responses in thyroid cells and protects the thyroid from oxidation induced by iodide overload. Surprisingly, it was also found that Nrf2 has a dramatic impact on both the basal abundance and the thyrotropin-inducible intrathyroidal abundance of thyroglobulin (Tg), the precursor protein of thyroid hormones. This effect is mediated by cell-autonomous regulation of Tg gene expression by Nrf2 via its direct binding to two evolutionarily conserved antioxidant response elements in an upstream enhancer. Yet, despite upregulating Tg levels, Nrf2 limits Tg iodination both under basal conditions and in response to excess iodide. CONCLUSIONS Nrf2 exerts pleiotropic roles in the thyroid gland to couple cell stress defense mechanisms to iodide metabolism and the thyroid hormone synthesis machinery, both under basal conditions and in response to excess iodide.
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Affiliation(s)
- Panos G. Ziros
- Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Ioannis G. Habeos
- Department of Internal Medicine, Division of Endocrinology, School of Medicine, University of Patras, Patras, Greece
| | | | - Eleni Ntalampyra
- Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Emmanuel Somm
- Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Cédric O. Renaud
- Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Massimo Bongiovanni
- Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland
| | - Ioannis P. Trougakos
- Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Thomas W. Kensler
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Pilar Santisteban
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas y Universidad Autónoma de Madrid, CIBERONC (ISCIII), Madrid, Spain
| | - Nancy Carrasco
- Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
| | - Carrie Ris-Stalpers
- Women's and Children's Clinic, Department of Obstetrics and Gynaecology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Elena Amendola
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli, Federico II, Naples, Italy
| | - Xiao-Hui Liao
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Luciano Rossich
- Nuclear Biochemistry Division, Argentine National Atomic Energy Commission, Buenos Aires, Argentina
- CONICET, Buenos Aires, Argentina
| | - Lisa Thomasz
- Nuclear Biochemistry Division, Argentine National Atomic Energy Commission, Buenos Aires, Argentina
- CONICET, Buenos Aires, Argentina
| | - Guillermo J. Juvenal
- Nuclear Biochemistry Division, Argentine National Atomic Energy Commission, Buenos Aires, Argentina
- CONICET, Buenos Aires, Argentina
| | - Samuel Refetoff
- Department of Medicine, The University of Chicago, Chicago, Illinois
- Department of Pediatrics, The University of Chicago, Chicago, Illinois
- Department of Committee on Genetics, The University of Chicago, Chicago, Illinois
| | - Gerasimos P. Sykiotis
- Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
- Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
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Mori H, Cardiff RD, Borowsky AD. Aging Mouse Models Reveal Complex Tumor-Microenvironment Interactions in Cancer Progression. Front Cell Dev Biol 2018; 6:35. [PMID: 29651417 PMCID: PMC5884881 DOI: 10.3389/fcell.2018.00035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 03/15/2018] [Indexed: 12/15/2022] Open
Abstract
Mouse models and genetically engineered mouse models (GEMM) are essential experimental tools for the understanding molecular mechanisms within complex biological systems. GEMM are especially useful for inferencing phenocopy information to genetic human diseases such as breast cancer. Human breast cancer modeling in mice most commonly employs mammary epithelial-specific promoters to investigate gene function(s) and, in particular, putative oncogenes. Models are specifically useful in the mammary epithelial cell in the context of the complete mammary gland environment. Gene targeted knockout mice including conditional targeting to specific mammary cells can reveal developmental defects in mammary organogenesis and demonstrate the importance of putative tumor suppressor genes. Some of these models demonstrate a non-traditional type of tumor suppression which involves interplay between the tumor susceptible cell and its host/environment. These GEMM help to reveal the processes of cancer progression beyond those intrinsic to cancer cells. Furthermore, the, analysis of mouse models requires appropriate consideration of mouse strain, background, and environmental factors. In this review, we compare aging-related factors in mouse models for breast cancer. We introduce databases of GEMM attributes and colony functional variations.
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Affiliation(s)
- Hidetoshi Mori
- Center for Comparative Medicine, University of California, Davis, Davis, CA, United States
| | - Robert D Cardiff
- Center for Comparative Medicine, University of California, Davis, Davis, CA, United States.,Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Alexander D Borowsky
- Center for Comparative Medicine, University of California, Davis, Davis, CA, United States.,Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Davis, CA, United States
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Pensold D, Zimmer G. Single-Cell Transcriptomics Reveals Regulators of Neuronal Migration and Maturation During Brain Development. J Exp Neurosci 2018; 12:1179069518760783. [PMID: 29551912 PMCID: PMC5846933 DOI: 10.1177/1179069518760783] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 02/01/2018] [Indexed: 11/22/2022] Open
Abstract
The correct establishment of inhibitory circuits is crucial for cortical functionality and defects during the development of γ-aminobutyric acid–expressing cortical interneurons contribute to the pathophysiology of psychiatric disorders. A critical developmental step is the migration of cortical interneurons from their site of origin within the subpallium to the cerebral cortex, orchestrated by intrinsic and extrinsic signals. In addition to genetic networks, epigenetic mechanisms such as DNA methylation by DNA methyltransferases (DNMTs) are suggested to drive stage-specific gene expression underlying developmental processes. The mosaic structure of the interneuron generating domains producing a variety of interneurons for diverse destinations complicates research on regulatory instances of cortical interneuron migration. To this end, we performed single-cell transcriptome analysis revealing Dnmt1 expression in subsets of migrating interneurons. We found that DNMT1 preserves the migratory morphology in part through transcriptional control over Pak6 that promotes neurite complexity in postmigratory cells. In addition, we identified Ccdc184, a gene of unknown function, to be highly expressed in postmitotic interneurons. Single-cell mRNA sequencing revealed a positive correlation of Ccdc184 with cell adhesion–associated genes pointing to potential implications of CCDC184 in processes relying on cell-cell adhesion–like migration or morphological differentiation of interneurons that deserves further investigations.
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Affiliation(s)
- Daniel Pensold
- Institute of Human Genetics, University Hospital Jena, Jena, Germany
| | - Geraldine Zimmer
- Institute of Human Genetics, University Hospital Jena, Jena, Germany
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Arends D, Hesse D, Brockmann GA. Invited review: Genetic and genomic mouse models for livestock research. Arch Anim Breed 2018. [DOI: 10.5194/aab-61-87-2018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Abstract. Knowledge about the function and functioning of single or
multiple interacting genes is of the utmost significance for understanding the
organism as a whole and for accurate livestock improvement through genomic
selection. This includes, but is not limited to, understanding the
ontogenetic and environmentally driven regulation of gene action
contributing to simple and complex traits. Genetically modified mice, in
which
the functions of single genes are annotated; mice with reduced genetic
complexity; and simplified structured populations are tools to gain
fundamental knowledge of inheritance patterns and whole system genetics and
genomics. In this review, we briefly describe existing mouse resources and
discuss their value for fundamental and applied research in livestock.
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50
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Mouse Genome Informatics (MGI) Is the International Resource for Information on the Laboratory Mouse. Methods Mol Biol 2018; 1757:141-161. [PMID: 29761459 DOI: 10.1007/978-1-4939-7737-6_7] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mouse Genome Informatics (MGI, http://www.informatics.jax.org/ ) web resources provide free access to meticulously curated information about the laboratory mouse. MGI's primary goal is to help researchers investigate the genetic foundations of human diseases by translating information from mouse phenotypes and disease models studies to human systems. MGI provides comprehensive phenotypes for over 50,000 mutant alleles in mice and provides experimental model descriptions for over 1500 human diseases. Curated data from scientific publications are integrated with those from high-throughput phenotyping and gene expression centers. Data are standardized using defined, hierarchical vocabularies such as the Mammalian Phenotype (MP) Ontology, Mouse Developmental Anatomy and the Gene Ontologies (GO). This chapter introduces you to Gene and Allele Detail pages and provides step-by-step instructions for simple searches and those that take advantage of the breadth of MGI data integration.
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