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Yang Z, Xiao Y, Shi Y, Liu L. Advances in the chemical synthesis of human proteoforms. SCIENCE CHINA. LIFE SCIENCES 2025:10.1007/s11427-024-2860-5. [PMID: 40210795 DOI: 10.1007/s11427-024-2860-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 02/03/2025] [Indexed: 04/12/2025]
Abstract
Access to structurally-defined human proteoforms is essential to the biochemical studies on human health and medicine. Chemical protein synthesis provides a bottom-up and atomic-resolution approach for the preparation of homogeneous proteoforms bearing any number of post-translational modifications of any structure, at any position, and in any combination. In this review, we summarize the development of chemical protein synthesis, focusing on the recent advances in synthetic methods, product characterizations, and biomedical applications. By analyzing the chemical protein synthesis studies on human proteoforms reported to date, this review demonstrates the significant methodological improvements that have taken place in the field of human proteoform synthesis, especially in the last decade. Our analysis shows that although further method development is needed, all the human proteoforms could be within reach in a cost-effective manner through a divide-and-conquer chemical protein synthesis strategy. The synthetic proteoforms have been increasingly used to support biomedical research, including spatial-temporal studies and interaction network analysis, activity quantification and mechanism elucidation, and the development and evaluation of diagnostics and therapeutics.
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Affiliation(s)
- Ziyi Yang
- New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, China
| | - Yudi Xiao
- New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, China
| | - Yang Shi
- New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, China
| | - Lei Liu
- New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, China.
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2
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Zuo X. Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging? Aging Dis 2025:AD.2025.0189. [PMID: 40249934 DOI: 10.14336/ad.2025.0189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 04/06/2025] [Indexed: 04/20/2025] Open
Abstract
Down syndrome (DS), caused by trisomy of chromosome 21 (HSA21), is a complex condition associated with neurodevelopmental impairments and accelerated brain aging, often culminating in early-onset Alzheimer's disease (AD). Central to this accelerated aging is mitochondrial imbalance, characterized by disrupted energy metabolism, increased oxidative stress, impaired dynamics, and defective quality control mechanisms like mitophagy. These abnormalities exacerbate neuronal vulnerability, driving cognitive decline and neurodegeneration. This review examines the genetic and biochemical underpinnings of mitochondrial dysfunction in DS, with a focus on the role of HSA21-encoded genes. We also highlight how mitochondrial dysfunction, amplified by oxidative stress and HSA21 gene dosage effects, converges with cellular senescence and neuroinflammation to accelerate Alzheimer-like pathology and brain aging in DS. Finally, we discuss emerging therapeutic strategies targeting mitochondrial pathways, which hold promise for mitigating neurodegenerative phenotypes and improving outcomes in DS.
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3
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Lattuada M, Capitoli G, Casati M, Lazzerotti A, Maglia O, Ferrari GM, Fossati C, Biondi A, Cattoni A, Corti P. Reference ranges for complete blood count in children and adolescents with Down syndrome. Front Pediatr 2024; 12:1510733. [PMID: 39722770 PMCID: PMC11668587 DOI: 10.3389/fped.2024.1510733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 11/20/2024] [Indexed: 12/28/2024] Open
Abstract
Introduction Down syndrome (DS) is linked to unique hematopoietic characteristics that affect complete blood count (CBC) parameters. Accurate reference ranges are essential for proper CBC interpretation in this population. Methods This retrospective study analyzed 2,627 CBCs from 481 DS patients, aged 31 days to 18 years, at a tertiary care center in Italy. Patients with significant comorbidities were excluded to ensure a homogeneous group. Results CBC parameters were assessed to establish age- and sex-specific reference ranges. Centile charts were developed for each parameter, and an online tool was created to allow clinicians to compare individual CBC results with the new ranges. Comparisons with the general pediatric population revealed significant differences, particularly in hemoglobin, hematocrit, and mean corpuscular volume, which were higher in DS (p < 0.001). In contrast, a significant percentage of CBCs showed white blood cell counts below the 2.5th centile of healthy controls (p < 0.001), except for the 31 days-1 year age group. A similar trend was observed for lymphocytes (p < 0.001) in the 1-18 years group. Discussion These newly established DS-specific reference ranges provide clinicians with a crucial tool for evaluating CBC results, potentially reducing unnecessary tests and emphasizing the need for tailored clinical assessment in managing this unique population.
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Affiliation(s)
- Martina Lattuada
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Giulia Capitoli
- Department of Medicine and Surgery, Bicocca Bioinformatics Biostatistics and Bioimaging Research Centre-B4, University of Milano-Bicocca, Monza, Italy
- Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Marco Casati
- Clinical Chemistry Laboratory Medicine, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | | | - Oscar Maglia
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | | | - Chiara Fossati
- Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Andrea Biondi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Alessandro Cattoni
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Paola Corti
- Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
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4
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Huang T, Fakurazi S, Cheah PS, Ling KH. Chromosomal and cellular therapeutic approaches for Down syndrome: A research update. Biochem Biophys Res Commun 2024; 735:150664. [PMID: 39260337 DOI: 10.1016/j.bbrc.2024.150664] [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: 06/01/2024] [Revised: 08/20/2024] [Accepted: 09/03/2024] [Indexed: 09/13/2024]
Abstract
In individuals with Down syndrome (DS), an additional HSA21 chromosome copy leads to the overexpression of a myriad of HSA21 genes, disrupting the transcription of the entire genome. This dysregulation in transcription and post-transcriptional modifications contributes to abnormal phenotypes across nearly all tissues and organs in DS individuals. The array of severe clinical symptoms associated with trisomy 21 poses a considerable challenge in the quest for a cure for DS. Fortunately, a wealth of research suggests that chromosome therapy, hinging on cutting-edge genome editing technologies, can potentially eliminate the extra copy of the human chromosome 21. Genome editing tools have demonstrated their efficacy in restoring trisomy to a normal diploid state in vitro DS cell models. Furthermore, we delve into the noteworthy findings in cellular therapy for DS, with recent studies showcasing the increasing feasibility of strategies involving stem cells and CAR T-cells to address corresponding clinical phenotypes.
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Affiliation(s)
- Tan Huang
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Sharida Fakurazi
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Pike-See Cheah
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia; Malaysian Research Institute on Ageing (MyAgeing(TM)), Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - King-Hwa Ling
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia; Malaysian Research Institute on Ageing (MyAgeing(TM)), Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
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5
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Citterio E, Ronchi AE. Deubiquitinases at the interplay between hematopoietic stem cell aging and myelodysplastic transformation. FEBS Lett 2024; 598:2807-2808. [PMID: 39108012 PMCID: PMC11586589 DOI: 10.1002/1873-3468.14991] [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: 12/04/2023] [Revised: 02/06/2024] [Accepted: 02/13/2024] [Indexed: 11/26/2024]
Abstract
Hematopoietic stem cells (HSC) maintain blood production throughout life. Nevertheless, HSC functionality deteriorates upon physiological aging leading to the increased prevalence of haematological diseases and hematopoietic malignancies in the elderly. Deubiquitinating enzymes (DUBs) by reverting protein ubiquitination ensure proper proteostasis, a key process in HSC maintenance and fitness.
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Affiliation(s)
- Elisabetta Citterio
- Department of Biotechnology and BiosciencesUniversity of Milano‐Bicocca20126MilanItaly
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6
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Ai H, He Z, Deng Z, Chu GC, Shi Q, Tong Z, Li JB, Pan M, Liu L. Structural and mechanistic basis for nucleosomal H2AK119 deubiquitination by single-subunit deubiquitinase USP16. Nat Struct Mol Biol 2024; 31:1745-1755. [PMID: 38918638 DOI: 10.1038/s41594-024-01342-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 05/29/2024] [Indexed: 06/27/2024]
Abstract
Epigenetic regulators have a crucial effect on gene expression based on their manipulation of histone modifications. Histone H2AK119 monoubiquitination (H2AK119Ub), a well-established hallmark in transcription repression, is dynamically regulated by the opposing activities of Polycomb repressive complex 1 (PRC1) and nucleosome deubiquitinases including the primary human USP16 and Polycomb repressive deubiquitinase (PR-DUB) complex. Recently, the catalytic mechanism for the multi-subunit PR-DUB complex has been described, but how the single-subunit USP16 recognizes the H2AK119Ub nucleosome and cleaves the ubiquitin (Ub) remains unknown. Here we report the cryo-EM structure of USP16-H2AK119Ub nucleosome complex, which unveils a fundamentally distinct mode of H2AK119Ub deubiquitination compared to PR-DUB, encompassing the nucleosome recognition pattern independent of the H2A-H2B acidic patch and the conformational heterogeneity in the Ub motif and the histone H2A C-terminal tail. Our work highlights the mechanism diversity of H2AK119Ub deubiquitination and provides a structural framework for understanding the disease-causing mutations of USP16.
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Affiliation(s)
- Huasong Ai
- New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
- Institute of Translational Medicine, School of Pharmacy, School of Chemistry and Chemical Engineering, National Center for Translational Medicine (Shanghai), Shanghai Jiao Tong University, Shanghai, China
| | - Zaozhen He
- New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Zhiheng Deng
- New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Guo-Chao Chu
- New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Qiang Shi
- New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Zebin Tong
- New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Jia-Bin Li
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Man Pan
- Institute of Translational Medicine, School of Pharmacy, School of Chemistry and Chemical Engineering, National Center for Translational Medicine (Shanghai), Shanghai Jiao Tong University, Shanghai, China.
| | - Lei Liu
- New Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China.
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7
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Ai H, Pan M, Liu L. Chemical Synthesis of Human Proteoforms and Application in Biomedicine. ACS CENTRAL SCIENCE 2024; 10:1442-1459. [PMID: 39220697 PMCID: PMC11363345 DOI: 10.1021/acscentsci.4c00642] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 09/04/2024]
Abstract
Limited understanding of human proteoforms with complex posttranslational modifications and the underlying mechanisms poses a major obstacle to research on human health and disease. This Outlook discusses opportunities and challenges of de novo chemical protein synthesis in human proteoform studies. Our analysis suggests that to develop a comprehensive, robust, and cost-effective methodology for chemical synthesis of various human proteoforms, new chemistries of the following types need to be developed: (1) easy-to-use peptide ligation chemistries allowing more efficient de novo synthesis of protein structural domains, (2) robust temporary structural support strategies for ligation and folding of challenging targets, and (3) efficient transpeptidative protein domain-domain ligation methods for multidomain proteins. Our analysis also indicates that accurate chemical synthesis of human proteoforms can be applied to the following aspects of biomedical research: (1) dissection and reconstitution of the proteoform interaction networks, (2) structural mechanism elucidation and functional analysis of human proteoform complexes, and (3) development and evaluation of drugs targeting human proteoforms. Overall, we suggest that through integrating chemical protein synthesis with in vivo functional analysis, mechanistic biochemistry, and drug development, synthetic chemistry would play a pivotal role in human proteoform research and facilitate the development of precision diagnostics and therapeutics.
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Affiliation(s)
- Huasong Ai
- New
Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life
Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology, Center for Synthetic and Systems Biology, Department
of Chemistry, Tsinghua University, Beijing 100084, China
- Institute
of Translational Medicine, School of Pharmacy, School of Chemistry
and Chemical Engineering, National Center for Translational Medicine
(Shanghai), Shanghai Jiao Tong University, Shanghai 200240, China
| | - Man Pan
- Institute
of Translational Medicine, School of Pharmacy, School of Chemistry
and Chemical Engineering, National Center for Translational Medicine
(Shanghai), Shanghai Jiao Tong University, Shanghai 200240, China
| | - Lei Liu
- New
Cornerstone Science Laboratory, Tsinghua-Peking Joint Center for Life
Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology, Center for Synthetic and Systems Biology, Department
of Chemistry, Tsinghua University, Beijing 100084, China
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8
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Escalante LE, Hose J, Howe H, Paulsen N, Place M, Gasch AP. Premature aging in aneuploid yeast is caused in part by aneuploidy-induced defects in Ribosome Quality Control. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.22.600216. [PMID: 38948718 PMCID: PMC11213126 DOI: 10.1101/2024.06.22.600216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Premature aging is a hallmark of Down syndrome, caused by trisomy of human chromosome 21, but the reason is unclear and difficult to study in humans. We used an aneuploid model in wild yeast to show that chromosome amplification disrupts nutrient-induced cell-cycle arrest, quiescence entry, and healthy aging, across genetic backgrounds and amplified chromosomes. We discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). Compared to euploids, aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates. Although they have normal proteasome capacity, aneuploids show signs of ubiquitin dysregulation, which impacts cyclin abundance to disrupt arrest. Remarkably, inducing ribosome stalling in euploids produces similar aberrations, while up-regulating limiting RQC subunits or proteins in ubiquitin metabolism alleviates many of the aneuploid defects. Our results provide implications for other aneuploidy disorders including Down syndrome.
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Affiliation(s)
- Leah E. Escalante
- Center for Genomic Science Innovation, University of Wisconsin-Madison, Madison, WI, 53706
| | - James Hose
- Center for Genomic Science Innovation, University of Wisconsin-Madison, Madison, WI, 53706
| | - Hollis Howe
- Center for Genomic Science Innovation, University of Wisconsin-Madison, Madison, WI, 53706
| | - Norah Paulsen
- Center for Genomic Science Innovation, University of Wisconsin-Madison, Madison, WI, 53706
| | - Michael Place
- Center for Genomic Science Innovation, University of Wisconsin-Madison, Madison, WI, 53706
- Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI, 53706
| | - Audrey P. Gasch
- Center for Genomic Science Innovation, University of Wisconsin-Madison, Madison, WI, 53706
- Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI, 53706
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53706
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9
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Dutcher HA, Hose J, Howe H, Rojas J, Gasch AP. The response to single-gene duplication implicates translation as a key vulnerability in aneuploid yeast. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.15.589582. [PMID: 38659764 PMCID: PMC11042342 DOI: 10.1101/2024.04.15.589582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Aneuploidy produces myriad consequences in health and disease, yet models of the deleterious effects of chromosome amplification are still widely debated. To distinguish the molecular determinants of aneuploidy stress, we measured the effects of duplicating individual genes in cells with varying chromosome duplications, in wild-type cells and cells sensitized to aneuploidy by deletion of RNA-binding protein Ssd1. We identified gene duplications that are nearly neutral in wild-type euploid cells but significantly deleterious in euploids lacking SSD1 or SSD1+ aneuploid cells with different chromosome duplications. Several of the most deleterious genes are linked to translation; in contrast, duplication of other translational regulators, including eI5Fa Hyp2, benefit ssd1Δ aneuploids over controls. Using modeling of aneuploid growth defects, we propose that the deleterious effects of aneuploidy emerge from an interaction between the cumulative burden of many amplified genes on a chromosome and a subset of duplicated genes that become toxic in that context. Our results suggest that the mechanism behind their toxicity is linked to a key vulnerability in translation in aneuploid cells. These findings provide a perspective on the dual impact of individual genes and overall genomic burden, offering new avenues for understanding aneuploidy and its cellular consequences.
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10
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Koch I, Slovik M, Zhang Y, Liu B, Rennie M, Konz E, Cogne B, Daana M, Davids L, Diets IJ, Gold NB, Holtz AM, Isidor B, Mor-Shaked H, Neira Fresneda J, Niederhoffer KY, Nizon M, Pfundt R, Simon M, Stegmann A, Guillen Sacoto MJ, Wevers M, Barakat TS, Yanovsky-Dagan S, Atanassov BS, Toth R, Gao C, Bustos F, Harel T. USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms. Life Sci Alliance 2024; 7:e202302258. [PMID: 38182161 PMCID: PMC10770416 DOI: 10.26508/lsa.202302258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 12/22/2023] [Accepted: 12/22/2023] [Indexed: 01/07/2024] Open
Abstract
Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.
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Affiliation(s)
- Intisar Koch
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Maya Slovik
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- Department of Genetics, Hadassah Medical Center, Jerusalem, Israel
| | - Yuling Zhang
- Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, PR China
| | - Bingyu Liu
- Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, PR China
| | - Martin Rennie
- School of Molecular Biosciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Emily Konz
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Benjamin Cogne
- Nantes Université, CHU de Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
- Nantes Université, CHU de Nantes, Service de Génétique médicale, Nantes, France
| | - Muhannad Daana
- Child Development Centers, Clalit Health Care Services, Jerusalem, Israel
| | - Laura Davids
- Department of Neurosciences, Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Illja J Diets
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
| | - Nina B Gold
- Massachusetts General Hospital for Children, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Alexander M Holtz
- Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, USA
| | - Bertrand Isidor
- Nantes Université, CHU de Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
- Nantes Université, CHU de Nantes, Service de Génétique médicale, Nantes, France
| | - Hagar Mor-Shaked
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- Department of Genetics, Hadassah Medical Center, Jerusalem, Israel
| | | | | | - Mathilde Nizon
- Nantes Université, CHU de Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
- Nantes Université, CHU de Nantes, Service de Génétique médicale, Nantes, France
| | - Rolph Pfundt
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
| | - Meh Simon
- Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
| | - Apa Stegmann
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands
| | | | - Marijke Wevers
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
| | - Tahsin Stefan Barakat
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | | | - Boyko S Atanassov
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Rachel Toth
- MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
| | - Chengjiang Gao
- Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, PR China
| | - Francisco Bustos
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
- Department of Pediatrics, University of South Dakota, Sioux Falls, SD, USA
| | - Tamar Harel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- Department of Genetics, Hadassah Medical Center, Jerusalem, Israel
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11
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Gan J, Pinto-Fernández A, Flierman D, Akkermans JJLL, O’Brien DP, Greenwood H, Scott HC, Fritz G, Knobeloch KP, Neefjes J, van Dam H, Ovaa H, Ploegh HL, Kessler BM, Geurink PP, Sapmaz A. USP16 is an ISG15 cross-reactive deubiquitinase that targets pro-ISG15 and ISGylated proteins involved in metabolism. Proc Natl Acad Sci U S A 2023; 120:e2315163120. [PMID: 38055744 PMCID: PMC10722975 DOI: 10.1073/pnas.2315163120] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 11/02/2023] [Indexed: 12/08/2023] Open
Abstract
Interferon-induced ubiquitin (Ub)-like modifier ISG15 covalently modifies host and viral proteins to restrict viral infections. Its function is counteracted by the canonical deISGylase USP18 or Ub-specific protease 18. Notwithstanding indications for the existence of other ISG15 cross-reactive proteases, these remain to be identified. Here, we identify deubiquitinase USP16 as an ISG15 cross-reactive protease by means of ISG15 activity-based profiling. Recombinant USP16 cleaved pro-ISG15 and ISG15 isopeptide-linked model substrates in vitro, as well as ISGylated substrates from cell lysates. Moreover, interferon-induced stimulation of ISGylation was increased by depletion of USP16. The USP16-dependent ISG15 interactome indicated that the deISGylating function of USP16 may regulate metabolic pathways. Targeted enzymes include malate dehydrogenase, cytoplasmic superoxide dismutase 1, fructose-bisphosphate aldolase A, and cytoplasmic glutamic-oxaloacetic transaminase 1. USP16 may thus contribute to the regulation of a subset of metabolism-related proteins during type-I interferon responses.
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Affiliation(s)
- Jin Gan
- Department of Cell and Chemical Biology, Division of Chemical Biology and Drug Discovery, Leiden University Medical Center, Leiden2333 ZC, The Netherlands
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA02115
| | - Adán Pinto-Fernández
- Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, OxfordOX3 7BN, United Kingdom
- Target Discovery Institute, Nuffield Department of Medicine, Centre for Medicines Discovery, University of Oxford, OxfordOX3 7FZ, United Kingdom
| | - Dennis Flierman
- Department of Cell and Chemical Biology, Division of Chemical Biology and Drug Discovery, Leiden University Medical Center, Leiden2333 ZC, The Netherlands
| | - Jimmy J. L. L. Akkermans
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center LUMC, Leiden2333 ZC, The Netherlands
| | - Darragh P. O’Brien
- Target Discovery Institute, Nuffield Department of Medicine, Centre for Medicines Discovery, University of Oxford, OxfordOX3 7FZ, United Kingdom
| | - Helene Greenwood
- Target Discovery Institute, Nuffield Department of Medicine, Centre for Medicines Discovery, University of Oxford, OxfordOX3 7FZ, United Kingdom
| | - Hannah Claire Scott
- Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, OxfordOX3 7BN, United Kingdom
| | - Günter Fritz
- Department of Cellular Microbiology, University of Hohenheim, Stuttgart70599, Germany
| | - Klaus-Peter Knobeloch
- Institute of Neuropathology, Faculty of Medicine, Department of Molecular Genetics, University of Freiburg, Freiburg79106, Germany
- Centre for Integrative Biological Signalling Studies, Department of Molecular Genetics, University of Freiburg, Freiburg79104, Germany
| | - Jacques Neefjes
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center LUMC, Leiden2333 ZC, The Netherlands
| | - Hans van Dam
- Department of Cell and Chemical Biology, Division of Chemical Biology and Drug Discovery, Leiden University Medical Center, Leiden2333 ZC, The Netherlands
| | - Huib Ovaa
- Department of Cell and Chemical Biology, Division of Chemical Biology and Drug Discovery, Leiden University Medical Center, Leiden2333 ZC, The Netherlands
| | - Hidde L. Ploegh
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA02115
| | - Benedikt M. Kessler
- Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, OxfordOX3 7BN, United Kingdom
- Target Discovery Institute, Nuffield Department of Medicine, Centre for Medicines Discovery, University of Oxford, OxfordOX3 7FZ, United Kingdom
| | - Paul P. Geurink
- Department of Cell and Chemical Biology, Division of Chemical Biology and Drug Discovery, Leiden University Medical Center, Leiden2333 ZC, The Netherlands
| | - Aysegul Sapmaz
- Department of Cell and Chemical Biology, Division of Chemical Biology and Drug Discovery, Leiden University Medical Center, Leiden2333 ZC, The Netherlands
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12
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O'Dea R, Kazi N, Hoffmann-Benito A, Zhao Z, Recknagel S, Wendrich K, Janning P, Gersch M. Molecular basis for ubiquitin/Fubi cross-reactivity in USP16 and USP36. Nat Chem Biol 2023; 19:1394-1405. [PMID: 37443395 PMCID: PMC10611586 DOI: 10.1038/s41589-023-01388-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023]
Abstract
Ubiquitin and ubiquitin-like proteins typically use distinct machineries to facilitate diverse functions. The immunosuppressive ubiquitin-like protein Fubi is synthesized as an N-terminal fusion to a ribosomal protein (Fubi-S30). Its proteolytic maturation by the nucleolar deubiquitinase USP36 is strictly required for translationally competent ribosomes. What endows USP36 with this activity, how Fubi is recognized and whether other Fubi proteases exist are unclear. Here, we report a chemical tool kit that facilitated the discovery of dual ubiquitin/Fubi cleavage activity in USP16 in addition to USP36 by chemoproteomics. Crystal structures of USP36 complexed with Fubi and ubiquitin uncover its substrate recognition mechanism and explain how other deubiquitinases are restricted from Fubi. Furthermore, we introduce Fubi C-terminal hydrolase measurements and reveal a synergistic role of USP16 in Fubi-S30 maturation. Our data highlight how ubiquitin/Fubi specificity is achieved in a subset of human deubiquitinases and open the door to a systematic investigation of the Fubi system.
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Affiliation(s)
- Rachel O'Dea
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Nafizul Kazi
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Alicia Hoffmann-Benito
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Zhou Zhao
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Sarah Recknagel
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Kim Wendrich
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
| | - Petra Janning
- Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany
| | - Malte Gersch
- Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.
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13
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Tong G, Chen Y, Chen X, Fan J, Zhu K, Hu Z, Li S, Zhu J, Feng J, Wu Z, Hu Z, Zhou B, Jin L, Chen H, Shen J, Cong W, Li X. FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice. Nat Commun 2023; 14:6107. [PMID: 37777507 PMCID: PMC10542385 DOI: 10.1038/s41467-023-41800-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 09/18/2023] [Indexed: 10/02/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) is a common complication occurs during hepatic resection and transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Here, we aim to explore the role of fibroblast growth factor 18 (FGF18) in hepatic IRI. In this work, we find that Hepatic stellate cells (HSCs) secrete FGF18 and alleviates hepatocytes injury. HSCs-specific FGF18 deletion largely aggravates hepatic IRI. Mechanistically, FGF18 treatment reduces the levels of ubiquitin carboxyl-terminal hydrolase 16 (USP16), leading to increased ubiquitination levels of Kelch Like ECH Associated Protein 1 (KEAP1) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, USP16 interacts and deubiquitinates KEAP1. More importantly, Nrf2 directly binds to the promoter of USP16 and forms a negative feedback loop with USP16. Collectively, our results show FGF18 alleviates hepatic IRI by USP16/KEAP1/Nrf2 signaling pathway in male mice, suggesting that FGF18 represents a promising therapeutic approach for hepatic IRI.
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Affiliation(s)
- Gaozan Tong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Yiming Chen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xixi Chen
- Department of pharmacy, Taizhou Central Hospital, Taizhou, Zhejiang, China
| | - Junfu Fan
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Kunxuan Zhu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - ZiJing Hu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Santie Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Junjie Zhu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Jianjun Feng
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhaohang Wu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhenyu Hu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Bin Zhou
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Litai Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Hui Chen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Jingling Shen
- Institute of Life Sciences, College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, China.
| | - Weitao Cong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China.
- Haihe Laboratory of Cell Ecosystem, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
| | - XiaoKun Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China.
- Haihe Laboratory of Cell Ecosystem, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
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14
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Page EC, Heatley SL, Rehn J, Thomas PQ, Yeung DT, White DL. Gain of chromosome 21 increases the propensity for P2RY8::CRLF2 acute lymphoblastic leukemia via increased HMGN1 expression. Front Oncol 2023; 13:1177871. [PMID: 37483494 PMCID: PMC10358767 DOI: 10.3389/fonc.2023.1177871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/15/2023] [Indexed: 07/25/2023] Open
Abstract
Acute lymphoblastic leukemia (ALL) patients with a gain of chromosome 21, intrachromosomal amplification of chromosome 21 (iAMP21), or Down syndrome (DS), have increased expression of genes in the DS critical region (DSCR) of chromosome 21, including the high-mobility group nucleosome-binding protein 1, HMGN1. Children with DS are predisposed to develop hematologic malignancies, providing insight into the role of chromosome 21 in the development of leukemias. A 320-kb deletion in the pseudoautosomal region of the X/Y chromosome in leukemic cells, resulting in a gene fusion between the purinergic receptor and cytokine receptor-like factor-2 (P2Y Receptor Family Member 8 (P2RY8)::CRLF2), is a common feature in ~60% of DS-ALL and ~40% of iAMP21 patients, suggesting a link between chromosome 21 and P2RY8::CRLF2. In an Australian cohort of pediatric B-ALL patients with P2RY8::CRLF2 (n = 38), eight patients harbored gain of chromosome 21 (+21), and two patients had iAMP21, resulting in a significantly increased HMGN1 expression. An inducible CRISPR/Cas9 system was used to model P2RY8::CRLF2 and investigate its cooperation with HMGN1. This model was then used to validate HMGN1 as an influencing factor for P2RY8::CRLF2 development. Using Cas9 to cleave the DNA at the pseudoautosomal region without directed repair, cells expressing HMGN1 favored repair, resulting in P2RY8::CRLF2 generation, compared with cells without HMGN1. CRISPR/Cas9 P2RY8::CRLF2 cells expressing HMGN1 exhibit increased proliferation, thymic stromal lymphopoietin receptor (TSLPR) expression, and JAK/STAT signaling, consistent with cells from patients with P2RY8::CRLF2. Our patient expression data and unique CRISPR/Cas9 modeling, when taken together, suggest that HMGN1 increases the propensity for P2RY8::CRLF2 development. This has important implications for patients with DS, +21, or iAMP21.
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Affiliation(s)
- Elyse C. Page
- Blood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- School of Biological Sciences, Faculty of Sciences, Engineering, and Technology, University of Adelaide, Adelaide, SA, Australia
- Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, Australia
| | - Susan L. Heatley
- Blood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, Australia
| | - Jacqueline Rehn
- Blood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, Australia
| | - Paul Q. Thomas
- Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, Australia
- SA Gene Editing Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - David T. Yeung
- Blood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, Australia
- Australasian Leukaemia and Lymphoma Group, Melbourne, VIC, Australia
- Department of Hematology, Royal Adelaide Hospital and SA Pathology, Adelaide, SA, Australia
- School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia
| | - Deborah L. White
- Blood Cancer Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- School of Biological Sciences, Faculty of Sciences, Engineering, and Technology, University of Adelaide, Adelaide, SA, Australia
- Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, Australia
- Australasian Leukaemia and Lymphoma Group, Melbourne, VIC, Australia
- Australian and New Zealand Children’s Hematology/Oncology Group (ANZCHOG), Clayton, VIC, Australia
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15
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Cai F, Song B, Yang Y, Liao H, Li R, Wang Z, Cao R, Chen H, Wang J, Wu Y, Zhang Y, Song W. USP25 contributes to defective neurogenesis and cognitive impairments. FASEB J 2023; 37:e22971. [PMID: 37171286 DOI: 10.1096/fj.202300057r] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/25/2023] [Accepted: 05/01/2023] [Indexed: 05/13/2023]
Abstract
Both Down syndrome (DS) individuals and animal models exhibit hypo-cellularity in hippocampus and neocortex indicated by enhanced neuronal death and compromised neurogenesis. Ubiquitin-specific peptidase 25 (USP25), a human chromosome 21 (HSA21) gene, encodes for a deubiquitinating enzyme overexpressed in DS patients. Dysregulation of USP25 has been associated with Alzheimer's phenotypes in DS, but its role in defective neurogenesis in DS has not been defined. In this study, we found that USP25 upregulation impaired cell cycle regulation during embryonic neurogenesis and cortical development. Overexpression of USP25 in hippocampus promoted the neural stem cells to glial cell fates and suppressed neuronal cell fate by altering the balance between cyclin D1 and cyclin D2, thus reducing neurogenesis in the hippocampus. USP25-Tg mice showed increased anxiety/depression-like behaviors and learning and memory deficits. These results suggested that USP25 overexpression resulted in defective neurogenesis and cognitive impairments, which could contribute to the pathogenesis of DS. USP25 may be a potential pharmaceutical target for DS.
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Affiliation(s)
- Fang Cai
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, Institute of Aging, School of Mental Health, Affiliated Kangning Hospital, The Second Affiliated Hospital, Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Townsend Family Laboratories, Department of Psychiatry, Graduate Program in Neuroscience, Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Beibei Song
- Townsend Family Laboratories, Department of Psychiatry, Graduate Program in Neuroscience, Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Yi Yang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, Institute of Aging, School of Mental Health, Affiliated Kangning Hospital, The Second Affiliated Hospital, Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Haikang Liao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, Institute of Aging, School of Mental Health, Affiliated Kangning Hospital, The Second Affiliated Hospital, Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ran Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, Institute of Aging, School of Mental Health, Affiliated Kangning Hospital, The Second Affiliated Hospital, Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhao Wang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, Institute of Aging, School of Mental Health, Affiliated Kangning Hospital, The Second Affiliated Hospital, Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ruixue Cao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, Institute of Aging, School of Mental Health, Affiliated Kangning Hospital, The Second Affiliated Hospital, Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huaqiu Chen
- National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Juelu Wang
- Townsend Family Laboratories, Department of Psychiatry, Graduate Program in Neuroscience, Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Yili Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, Institute of Aging, School of Mental Health, Affiliated Kangning Hospital, The Second Affiliated Hospital, Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yun Zhang
- National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Weihong Song
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, Institute of Aging, School of Mental Health, Affiliated Kangning Hospital, The Second Affiliated Hospital, Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Townsend Family Laboratories, Department of Psychiatry, Graduate Program in Neuroscience, Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada
- National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China
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16
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Wang H, Langlais D, Nijnik A. Histone H2A deubiquitinases in the transcriptional programs of development and hematopoiesis: a consolidated analysis. Int J Biochem Cell Biol 2023; 157:106384. [PMID: 36738766 DOI: 10.1016/j.biocel.2023.106384] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 01/31/2023] [Indexed: 02/05/2023]
Abstract
Monoubiquitinated lysine 119 of histone H2A (H2AK119ub) is a highly abundant epigenetic mark, associated with gene repression and deposited on chromatin by the polycomb repressor complex 1 (PRC1), which is an essential regulator of diverse transcriptional programs in mammalian development and tissue homeostasis. While multiple deubiquitinases (DUBs) with catalytic activity for H2AK119ub (H2A-DUBs) have been identified, we lack systematic analyses of their roles and cross-talk in transcriptional regulation. Here, we address H2A-DUB functions in epigenetic regulation of mammalian development and tissue maintenance by conducting a meta-analysis of 248 genomics datasets from 32 independent studies, focusing on the mouse model and covering embryonic stem cells (ESCs), hematopoietic, and immune cell lineages. This covers all the publicly available datasets that map genomic H2A-DUB binding and H2AK119ub distributions (ChIP-Seq), and all datasets assessing dysregulation in gene expression in the relevant H2A-DUB knockout models (RNA-Seq). Many accessory datasets for PRC1-2 and DUB-interacting proteins are also analyzed and interpreted, as well as further data assessing chromatin accessibility (ATAC-Seq) and transcriptional activity (RNA-seq). We report co-localization in the binding of H2A-DUBs BAP1, USP16, and to a lesser extent others that is conserved across different cell-types, and also the enrichment of antagonistic PRC1-2 protein complexes at the same genomic locations. Such conserved sites enriched for the H2A-DUBs and PRC1-2 are proximal to transcriptionally active genes that engage in housekeeping cellular functions. Nevertheless, they exhibit H2AK119ub levels significantly above the genomic average that can undergo further increase with H2A-DUB knockout. This indicates a cooperation between H2A-DUBs and PRC1-2 in the modulation of housekeeping transcriptional programs, conserved across many cell types, likely operating through their antagonistic effects on H2AK119ub and the regulation of local H2AK119ub turnover. Our study further highlights existing knowledge gaps and discusses important directions for future work.
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Affiliation(s)
- HanChen Wang
- Department of Physiology, McGill University, Montreal, QC, Canada; McGill University Research Centre on Complex Traits, McGill University, QC, Canada
| | - David Langlais
- McGill University Research Centre on Complex Traits, McGill University, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada; McGill Genome Centre, Montreal, QC, Canada.
| | - Anastasia Nijnik
- Department of Physiology, McGill University, Montreal, QC, Canada; McGill University Research Centre on Complex Traits, McGill University, QC, Canada.
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17
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Zheng J, Chen C, Guo C, Caba C, Tong Y, Wang H. The Pleiotropic Ubiquitin-Specific Peptidase 16 and Its Many Substrates. Cells 2023; 12:886. [PMID: 36980227 PMCID: PMC10047310 DOI: 10.3390/cells12060886] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 02/22/2023] [Accepted: 03/09/2023] [Indexed: 03/16/2023] Open
Abstract
Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that plays a role in the regulation of gene expression, cell cycle progression, and various other functions. It was originally identified as the major deubiquitinase for histone H2A and has since been found to deubiquitinate a range of other substrates, including proteins from both the cytoplasm and nucleus. USP16 is phosphorylated when cells enter mitosis and dephosphorylated during the metaphase/anaphase transition. While much of USP16 is localized in the cytoplasm, separating the enzyme from its substrates is considered an important regulatory mechanism. Some of the functions that USP16 has been linked to include DNA damage repair, immune disease, tumorigenesis, protein synthesis, coronary artery health, and male infertility. The strong connection to immune response and the fact that multiple oncogene products are substrates of USP16 suggests that USP16 may be a potential therapeutic target for the treatment of certain human diseases.
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Affiliation(s)
- Jiahuan Zheng
- Department of Internal Medicine, Division of Hematology, Oncology, and Palliative Care, Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- Department of Obstetrics and Gynecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
| | - Chunxu Chen
- Department of Bioengineering, School of Engineering, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Chunqing Guo
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Cody Caba
- Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada
| | - Yufeng Tong
- Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada
| | - Hengbin Wang
- Department of Internal Medicine, Division of Hematology, Oncology, and Palliative Care, Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
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18
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Shen J, Lin X, Dai F, Chen G, Lin H, Fang B, Liu H. Ubiquitin-specific peptidases: Players in bone metabolism. Cell Prolif 2023:e13444. [PMID: 36883930 PMCID: PMC10392067 DOI: 10.1111/cpr.13444] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/22/2023] [Accepted: 02/28/2023] [Indexed: 03/09/2023] Open
Abstract
Osteoporosis is an ageing-related disease, that has become a major public health problem and its pathogenesis has not yet been fully elucidated. Substantial evidence suggests a strong link between overall age-related disease progression and epigenetic modifications throughout the life cycle. As an important epigenetic modification, ubiquitination is extensively involved in various physiological processes, and its role in bone metabolism has attracted increasing attention. Ubiquitination can be reversed by deubiquitinases, which counteract protein ubiquitination degradation. As the largest and most structurally diverse cysteinase family of deubiquitinating enzymes, ubiquitin-specific proteases (USPs), comprising the largest and most structurally diverse cysteine kinase family of deubiquitinating enzymes, have been found to be important players in maintaining the balance between bone formation and resorption. The aim of this review is to explore recent findings highlighting the regulatory functions of USPs in bone metabolism and provide insight into the molecular mechanisms governing their actions during bone loss. An in-deep understanding of USPs-mediated regulation of bone formation and bone resorption will provide a scientific rationale for the discovery and development of novel USP-targeted therapeutic strategies for osteoporosis.
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Affiliation(s)
- Jianlin Shen
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, China
| | - Xiaoning Lin
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, China
| | - Feifei Dai
- School of Medicine, Putian Universtiy, Putian, China
| | - Guoli Chen
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, China
| | - Haibin Lin
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, China
| | - Bangjiang Fang
- Department of Emergency, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Emergency and Critical Care Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huan Liu
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, China
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19
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Marino N, Putignano G, Cappilli S, Chersoni E, Santuccione A, Calabrese G, Bischof E, Vanhaelen Q, Zhavoronkov A, Scarano B, Mazzotta AD, Santus E. Towards AI-driven longevity research: An overview. FRONTIERS IN AGING 2023; 4:1057204. [PMID: 36936271 PMCID: PMC10018490 DOI: 10.3389/fragi.2023.1057204] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/06/2023] [Indexed: 03/06/2023]
Abstract
While in the past technology has mostly been utilized to store information about the structural configuration of proteins and molecules for research and medical purposes, Artificial Intelligence is nowadays able to learn from the existing data how to predict and model properties and interactions, revealing important knowledge about complex biological processes, such as aging. Modern technologies, moreover, can rely on a broader set of information, including those derived from the next-generation sequencing (e.g., proteomics, lipidomics, and other omics), to understand the interactions between human body and the external environment. This is especially relevant as external factors have been shown to have a key role in aging. As the field of computational systems biology keeps improving and new biomarkers of aging are being developed, artificial intelligence promises to become a major ally of aging research.
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Affiliation(s)
- Nicola Marino
- Women’s Brain Project (WBP), Gunterhausen, Switzerland
| | | | - Simone Cappilli
- Dermatology, Catholic University of the Sacred Heart, Rome, Italy
- UOC of Dermatology, Department of Abdominal and Endocrine Metabolic Medical and Surgical Sciences, A. Gemelli University Hospital Foundation-IRCCS, Rome, Italy
| | - Emmanuele Chersoni
- Department of Chinese and Bilingual Studies, The Hong Kong Polytechnic University, Hong Kong, China
| | | | - Giuliana Calabrese
- Department of Translational Medicine and Surgery, CatholicUniversity of the Sacred Heart, Rome, Italy
| | - Evelyne Bischof
- Insilico Medicine Hong Kong Ltd., New Territories, Hong Kong SAR, China
| | - Quentin Vanhaelen
- Insilico Medicine Hong Kong Ltd., New Territories, Hong Kong SAR, China
| | - Alex Zhavoronkov
- Insilico Medicine Hong Kong Ltd., New Territories, Hong Kong SAR, China
| | - Bryan Scarano
- Department of Translational Medicine and Surgery, CatholicUniversity of the Sacred Heart, Rome, Italy
| | - Alessandro D. Mazzotta
- Department of Digestive, Oncological and Metabolic Surgery, Institute Mutualiste Montsouris, Paris, France
- Biorobotics Institute, Scuola Superiore Sant’anna, Pisa, Italy
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20
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Jolly LA, Kumar R, Penzes P, Piper M, Gecz J. The DUB Club: Deubiquitinating Enzymes and Neurodevelopmental Disorders. Biol Psychiatry 2022; 92:614-625. [PMID: 35662507 PMCID: PMC10084722 DOI: 10.1016/j.biopsych.2022.03.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 02/28/2022] [Accepted: 03/28/2022] [Indexed: 02/08/2023]
Abstract
Protein ubiquitination is a widespread, multifunctional, posttranslational protein modification, best known for its ability to direct protein degradation via the ubiquitin proteasome system (UPS). Ubiquitination is also reversible, and the human genome encodes over 90 deubiquitinating enzymes (DUBs), many of which appear to target specific subsets of ubiquitinated proteins. This review focuses on the roles of DUBs in neurodevelopmental disorders (NDDs). We present the current genetic evidence connecting 12 DUBs to a range of NDDs and the functional studies implicating at least 19 additional DUBs as candidate NDD genes. We highlight how the study of DUBs in NDDs offers critical insights into the role of protein degradation during brain development. Because one of the major known functions of a DUB is to antagonize the UPS, loss of function of DUB genes has been shown to culminate in loss of abundance of its protein substrates. The identification and study of NDD DUB substrates in the developing brain is revealing that they regulate networks of proteins that themselves are encoded by NDD genes. We describe the new technologies that are enabling the full resolution of DUB protein networks in the developing brain, with the view that this knowledge can direct the development of new therapeutic paradigms. The fact that the abundance of many NDD proteins is regulated by the UPS presents an exciting opportunity to combat NDDs caused by haploinsufficiency, because the loss of abundance of NDD proteins can be potentially rectified by antagonizing their UPS-based degradation.
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Affiliation(s)
- Lachlan A Jolly
- University of Adelaide and Robinson Research Institute, Adelaide, South Australia, Australia.
| | - Raman Kumar
- University of Adelaide and Robinson Research Institute, Adelaide, South Australia, Australia
| | - Peter Penzes
- Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Michael Piper
- School of Biomedical Sciences and Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
| | - Jozef Gecz
- University of Adelaide and Robinson Research Institute, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
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21
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Sharma V, Nehra S, Do LH, Ghosh A, Deshpande AJ, Singhal N. Biphasic cell cycle defect causes impaired neurogenesis in down syndrome. Front Genet 2022; 13:1007519. [PMID: 36313423 PMCID: PMC9596798 DOI: 10.3389/fgene.2022.1007519] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 09/30/2022] [Indexed: 11/29/2022] Open
Abstract
Impaired neurogenesis in Down syndrome (DS) is characterized by reduced neurons, increased glial cells, and delayed cortical lamination. However, the underlying cause for impaired neurogenesis in DS is not clear. Using both human and mouse iPSCs, we demonstrate that DS impaired neurogenesis is due to biphasic cell cycle dysregulation during the generation of neural progenitors from iPSCs named the “neurogenic stage” of neurogenesis. Upon neural induction, DS cells showed reduced proliferation during the early phase followed by increased proliferation in the late phase of the neurogenic stage compared to control cells. While reduced proliferation in the early phase causes reduced neural progenitor pool, increased proliferation in the late phase leads to delayed post mitotic neuron generation in DS. RNAseq analysis of late-phase DS progenitor cells revealed upregulation of S phase-promoting regulators, Notch, Wnt, Interferon pathways, and REST, and downregulation of several genes of the BAF chromatin remodeling complex. NFIB and POU3F4, neurogenic genes activated by the interaction of PAX6 and the BAF complex, were downregulated in DS cells. ChIPseq analysis of late-phase neural progenitors revealed aberrant PAX6 binding with reduced promoter occupancy in DS cells. Together, these data indicate that impaired neurogenesis in DS is due to biphasic cell cycle dysregulation during the neurogenic stage of neurogenesis.
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Affiliation(s)
| | | | - Long H. Do
- Department of Neuroscience, University of California, San Diego, San Diego, CA, United States
| | - Anwesha Ghosh
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | | | - Nishant Singhal
- National Centre for Cell Science, Pune, India
- *Correspondence: Nishant Singhal,
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22
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Li L, Zhou A, Wei Y, Liu F, Li P, Fang R, Ma L, Zhang S, Wang L, Liu J, Richard HT, Chen Y, Wang H, Huang S. Critical role of lncEPAT in coupling dysregulated EGFR pathway and histone H2A deubiquitination during glioblastoma tumorigenesis. SCIENCE ADVANCES 2022; 8:eabn2571. [PMID: 36197973 PMCID: PMC9534510 DOI: 10.1126/sciadv.abn2571] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 08/18/2022] [Indexed: 06/16/2023]
Abstract
Histone 2A (H2A) monoubiquitination is a fundamental epigenetics mechanism of gene expression, which plays a critical role in regulating cell fate. However, it is unknown if H2A ubiquitination is involved in EGFR-driven tumorigenesis. In the current study, we have characterized a previously unidentified oncogenic lncRNA (lncEPAT) that mediates the integration of the dysregulated EGFR pathway with H2A deubiquitination in tumorigenesis. LncEPAT was induced by the EGFR pathway, and high-level lncEPAT expression positively correlated with the glioma grade and predicted poor survival of glioma patients. Mass spectrometry analyses revealed that lncEPAT specifically interacted with deubiquitinase USP16. LncEPAT inhibited USP16's recruitment to chromatin, thereby blocking USP16-mediated H2A deubiquitination and repressing target gene expression, including CDKN1A and CLUSTERIN. Depletion of lncEPAT promoted USP16-induced cell cycle arrest and cellular senescence, and then repressed GBM cell tumorigenesis. Thus, the EGFR-lncEPAT-ubH2A coupling represents a previously unidentified mechanism for epigenetic gene regulation and senescence resistance during GBM tumorigenesis.
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Affiliation(s)
- Linlin Li
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Aidong Zhou
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yanjun Wei
- Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Feng Liu
- Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA
| | - Peng Li
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Runping Fang
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Li Ma
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sicong Zhang
- Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York City, NY 10065, USA
| | - Longqiang Wang
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jinze Liu
- Department of Biostatistics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Hope T. Richard
- VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- Department of Pathology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Yiwen Chen
- Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Quantitative Sciences Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Hengbin Wang
- VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- Department of Internal Medicine, Division of Hematology, Oncology and Palliative Care, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Suyun Huang
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- Virginia Commonwealth University Institute of Molecular Medicine, Richmond, VA 23298, USA
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23
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Rong Y, Zhu YZ, Yu JL, Wu YW, Ji SY, Zhou Y, Jiang Y, Jin J, Fan HY, Shen L, Sha QQ. USP16-mediated histone H2A lysine-119 deubiquitination during oocyte maturation is a prerequisite for zygotic genome activation. Nucleic Acids Res 2022; 50:5599-5616. [PMID: 35640597 PMCID: PMC9178006 DOI: 10.1093/nar/gkac468] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/12/2022] [Accepted: 05/17/2022] [Indexed: 12/12/2022] Open
Abstract
Maternal-to-zygotic transition (MZT) is the first and key step in the control of animal development and intimately related to changes in chromatin structure and histone modifications. H2AK119ub1, an important epigenetic modification in regulating chromatin configuration and function, is primarily catalyzed by PRC1 and contributes to resistance to transcriptional reprogramming in mouse embryos. In this study, the genome-wide dynamic distribution of H2AK119ub1 during MZT in mice was investigated using chromosome immunoprecipitation and sequencing. The results indicated that H2AK119ub1 accumulated in fully grown oocytes and was enriched at the TSSs of maternal genes, but was promptly declined after meiotic resumption at genome-wide including the TSSs of early zygotic genes, by a previously unidentified mechanism. Genetic evidences indicated that ubiquitin-specific peptidase 16 (USP16) is the major deubiquitinase for H2AK119ub1 in mouse oocytes. Conditional knockout of Usp16 in oocytes did not impair their survival, growth, or meiotic maturation. However, oocytes lacking USP16 have defects when undergoing zygotic genome activation or gaining developmental competence after fertilization, potentially associated with high levels of maternal H2AK119ub1 deposition on the zygotic genomes. Taken together, H2AK119ub1 level is declined during oocyte maturation by an USP16-dependent mechanism, which ensures zygotic genome reprogramming and transcriptional activation of essential early zygotic genes.
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Affiliation(s)
- Yan Rong
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province; Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China
- MOE Key Laboratory for Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Ye-Zhang Zhu
- MOE Key Laboratory for Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Jia-li Yu
- MOE Key Laboratory for Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Yun-Wen Wu
- MOE Key Laboratory for Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Shu-Yan Ji
- MOE Key Laboratory for Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Yong Zhou
- Fertility Preservation Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou 510317, China
| | - Yu Jiang
- MOE Key Laboratory for Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Jin Jin
- MOE Key Laboratory for Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Heng-Yu Fan
- MOE Key Laboratory for Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Li Shen
- MOE Key Laboratory for Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Qian-Qian Sha
- Fertility Preservation Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou 510317, China
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24
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Hamaguchi Y, Kondoh T, Fukuda M, Yamasaki K, Yoshiura KI, Moriuchi H, Morii M, Muramatsu M, Minami T, Osato M. Leukopenia, macrocytosis, and thrombocytopenia occur in young adults with Down syndrome. Gene 2022; 835:146663. [PMID: 35690282 DOI: 10.1016/j.gene.2022.146663] [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: 11/09/2021] [Revised: 05/03/2022] [Accepted: 06/06/2022] [Indexed: 11/04/2022]
Abstract
Down syndrome (DS) is a common congenital disorder caused by trisomy 21. Due to the increase in maternal age with population aging and advances in medical treatment for fatal complications in their early childhood, the prevalence and life expectancy of DS individuals have greatly increased. Despite this rise in the number of DS adults, their hematological status remains poorly examined. Here, we report that three hematological abnormalities, leukopenia, macrocytosis, and thrombocytopenia, develop as adult DS-associated features. Multi- and uni-variate analyses on hematological data collected from 51 DS and 60 control adults demonstrated that young adults with DS are at significantly higher risk of (i) myeloid-dominant leukopenia, (ii) macrocytosis characterized by high mean cell volume (MCV) of erythrocytes, and (iii) lower platelet counts than the control. Notably, these features were more pronounced with age. Further analyses on DS adults would provide a deeper understanding and novel research perspectives for multiple aging-related disorders in the general population.
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Affiliation(s)
- Yo Hamaguchi
- Department of Pediatrics, National Hospital Organization Nagasaki Medical Center, Omura, Japan; Department of Human Genetics, Atomic Bomb Disease Institute, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tatsuro Kondoh
- The Misakaenosono Mutsumi Developmental, Medical and Welfare Center, Nagasaki, Japan
| | - Masafumi Fukuda
- The Misakaenosono Mutsumi Developmental, Medical and Welfare Center, Nagasaki, Japan
| | - Kazumi Yamasaki
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Japan
| | - Koh-Ichiro Yoshiura
- Department of Human Genetics, Atomic Bomb Disease Institute, Division of Advanced Preventive Medical Sciences and Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Hiroyuki Moriuchi
- Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mariko Morii
- International Research Center for Medical Sciences, Kumamoto University, Japan
| | - Masashi Muramatsu
- Center for Animal Resources and Development, Kumamoto University, Japan
| | - Takashi Minami
- Center for Animal Resources and Development, Kumamoto University, Japan
| | - Motomi Osato
- International Research Center for Medical Sciences, Kumamoto University, Japan; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pediatrics, National University of Singapore, Singapore.
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25
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Cellular senescence in the Aging Brain: A promising target for neurodegenerative diseases. Mech Ageing Dev 2022; 204:111675. [DOI: 10.1016/j.mad.2022.111675] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/24/2022] [Accepted: 04/07/2022] [Indexed: 01/10/2023]
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26
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Reinitz F, Chen EY, Nicolis di Robilant B, Chuluun B, Antony J, Jones RC, Gubbi N, Lee K, Ho WHD, Kolluru SS, Qian D, Adorno M, Piltti K, Anderson A, Monje M, Heller HC, Quake SR, Clarke MF. Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model. eLife 2022; 11:66037. [PMID: 35311644 PMCID: PMC9122497 DOI: 10.7554/elife.66037] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/17/2022] [Indexed: 11/23/2022] Open
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.
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Affiliation(s)
- Felicia Reinitz
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Elizabeth Y Chen
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Benedetta Nicolis di Robilant
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | | | - Jane Antony
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Robert C Jones
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Neha Gubbi
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Karen Lee
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - William Hai Dang Ho
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Sai Saroja Kolluru
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Dalong Qian
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Maddalena Adorno
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Katja Piltti
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States
| | - Aileen Anderson
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States
| | - Michelle Monje
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - H Craig Heller
- Department of Biology, Stanford University, Stanford, United States
| | - Stephen R Quake
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Michael F Clarke
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
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27
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Boucher AC, Caldwell KJ, Crispino JD, Flerlage JE. Clinical and biological aspects of myeloid leukemia in Down syndrome. Leukemia 2021; 35:3352-3360. [PMID: 34518645 PMCID: PMC8639661 DOI: 10.1038/s41375-021-01414-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 02/08/2023]
Abstract
Children with Down syndrome are at an elevated risk of leukemia, especially myeloid leukemia (ML-DS). This malignancy is frequently preceded by transient abnormal myelopoiesis (TAM), which is self-limited expansion of fetal liver-derived megakaryocyte progenitors. An array of international studies has led to consensus in treating ML-DS with reduced-intensity chemotherapy, leading to excellent outcomes. In addition, studies performed in the past 20 years have revealed many of the genetic and epigenetic features of the tumors, including GATA1 mutations that are arguably associated with all cases of both TAM and ML-DS. Despite these advances in understanding the clinical and biological aspects of ML-DS, little is known about the mechanisms of relapse. Upon relapse, patients face a poor outcome, and there is no consensus on treatment. Future studies need to be focused on this challenging aspect of leukemia in children with DS.
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Affiliation(s)
- Austin C Boucher
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Kenneth J Caldwell
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - John D Crispino
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
| | - Jamie E Flerlage
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
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28
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Zhang J, Lu X, MoghaddamKohi S, Shi L, Xu X, Zhu WG. Histone lysine modifying enzymes and their critical roles in DNA double-strand break repair. DNA Repair (Amst) 2021; 107:103206. [PMID: 34411909 DOI: 10.1016/j.dnarep.2021.103206] [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: 03/29/2021] [Revised: 07/24/2021] [Accepted: 08/05/2021] [Indexed: 10/20/2022]
Abstract
Cells protect the integrity of the genome against DNA double-strand breaks through several well-characterized mechanisms including nonhomologous end-joining repair, homologous recombination repair, microhomology-mediated end-joining and single-strand annealing. However, aberrant DNA damage responses (DDRs) lead to genome instability and tumorigenesis. Clarification of the mechanisms underlying the DDR following lethal damage will facilitate the identification of therapeutic targets for cancer. Histones are small proteins that play a major role in condensing DNA into chromatin and regulating gene function. Histone modifications commonly occur in several residues including lysine, arginine, serine, threonine and tyrosine, which can be acetylated, methylated, ubiquitinated and phosphorylated. Of these, lysine modifications have been extensively explored during DDRs. Here, we focus on discussing the roles of lysine modifying enzymes involved in acetylation, methylation, and ubiquitination during the DDR. We provide a comprehensive understanding of the basis of potential epigenetic therapies driven by histone lysine modifications.
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Affiliation(s)
- Jun Zhang
- Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen, 518055, China
| | - Xiaopeng Lu
- Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen, 518055, China
| | - Sara MoghaddamKohi
- Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen, 518055, China
| | - Lei Shi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
| | - Xingzhi Xu
- Department of Cell Biology and Medical Genetics, School of Medicine, Shenzhen University, Shenzhen, 518055, China.
| | - Wei-Guo Zhu
- Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen, 518055, China.
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29
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Xu G, Yang Z, Ding Y, Liu Y, Zhang L, Wang B, Tang M, Jing T, Jiao K, Xu X, Chen Z, Xiang L, Xu C, Fu Y, Zhao X, Jin W, Liu Y. The deubiquitinase USP16 functions as an oncogenic factor in K-RAS-driven lung tumorigenesis. Oncogene 2021; 40:5482-5494. [PMID: 34294846 DOI: 10.1038/s41388-021-01964-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 07/08/2021] [Accepted: 07/13/2021] [Indexed: 02/07/2023]
Abstract
K-RAS mutation and molecular alterations of its surrogates function essentially in lung tumorigenesis and malignant progression. However, it remains elusive how tumor-promoting and deleterious events downstream of K-RAS signaling are coordinated in lung tumorigenesis. Here, we show that USP16, a deubiquitinase involved in various biological processes, functions as a promoter for the development of K-RAS-driven lung tumor. Usp16 deletion significantly attenuates K-rasG12D-mutation-induced lung tumorigenesis in mice. USP16 upregulation upon RAS activation averts reactive oxygen species (ROS)-induced p38 activation that would otherwise detrimentally influence the survival and proliferation of tumor cells. In addition, USP16 interacts with and deubiquitinates JAK1, and thereby promoting lung tumor growth by augmenting JAK1 signaling. Therefore, our results reveal that USP16 functions critically in the K-RAS-driven lung tumorigenesis through modulating the strength of p38 and JAK1 signaling.
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Affiliation(s)
- Guiqin Xu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhaojuan Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yizong Ding
- Department of Thoracic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yun Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Boshi Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming Tang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tiantian Jing
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kun Jiao
- Shanghai Jiao Tong University School of Biomedical Engineering, Shanghai, China
| | - Xiaoli Xu
- Shanghai Jiao Tong University School of Biomedical Engineering, Shanghai, China
| | - Zehong Chen
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lvzhu Xiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Xu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yujie Fu
- Department of Thoracic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaojing Zhao
- Department of Thoracic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weilin Jin
- Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, People's Republic of China
| | - Yongzhong Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Tanuma-Takahashi A, Inoue M, Kajiwara K, Takagi R, Yamaguchi A, Samura O, Akutsu H, Sago H, Kiyono T, Okamoto A, Umezawa A. Restoration of keratinocytic phenotypes in autonomous trisomy-rescued cells. Stem Cell Res Ther 2021; 12:476. [PMID: 34433490 PMCID: PMC8390253 DOI: 10.1186/s13287-021-02448-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 06/06/2021] [Indexed: 11/10/2022] Open
Abstract
Background An extra copy of chromosome 21 in humans can alter cellular phenotypes as well as immune and metabolic systems. Down syndrome is associated with many health-related problems and age-related disorders including dermatological abnormalities. However, few studies have focused on the impact of trisomy 21 (T21) on epidermal stem cells and progenitor cell dysfunction. Here, we investigated the differences in keratinocytic characteristics between Down syndrome and euploid cells by differentiating cells from trisomy 21-induced pluripotent stem cells (T21-iPSCs) and autonomous rescued disomy 21-iPSCs (D21-iPSCs). Methods Our protocol for keratinocytic differentiation of T21-iPSCs and D21-iPSCs was employed. For propagation of T21- and D21-iPSC-derived keratinocytes and cell sheet formation, the culture medium supplemented with Rho kinase inhibitor on mouse feeder cells was introduced as growth rate decreased. Before passaging, selection of a keratinocytic population with differential dispase reactivity was performed. Three-dimensional (3D) air-liquid interface was performed in order to evaluate the ability of iPSC-derived keratinocytes to differentiate and form stratified squamous epithelium. Results Trisomy-rescued disomy 21-iPSCs were capable of epidermal differentiation and expressed keratinocytic markers such as KRT14 and TP63 upon differentiation compared to trisomy 21-iPSCs. The lifespan of iPSC-derived keratinocytes could successfully be extended on mouse feeder cells in media containing Rho kinase inhibitor, to more than 34 population doublings over a period of 160 days. Dispase-based purification of disomy iPSC-derived keratinocytes contributed epidermal sheet formation. The trisomy-rescued disomy 21-iPSC-derived keratinocytes with an expanded lifespan generated 3D skin in combination with a dermal fibroblast component. Conclusions Keratinocytes derived from autonomous trisomy-rescued iPSC have the ability of stratification for manufacturing 3D skin with restoration of keratinocytic functions. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02448-w.
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Affiliation(s)
- Akiko Tanuma-Takahashi
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.,Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, 105-8471, Japan
| | - Momoko Inoue
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.,Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, 105-8471, Japan
| | - Kazuhiro Kajiwara
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.,Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, 105-8471, Japan
| | - Ryo Takagi
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.,Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, 162-8666, Japan
| | - Ayumi Yamaguchi
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Osamu Samura
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, 105-8471, Japan
| | - Hidenori Akutsu
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Haruhiko Sago
- Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, 157-8535, Japan
| | - Tohru Kiyono
- Project for Prevention of HPV-related Cancer, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, 277-8577, Japan
| | - Aikou Okamoto
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, 105-8471, Japan
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
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31
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Barabino SML, Citterio E, Ronchi AE. Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancers (Basel) 2021; 13:cancers13153753. [PMID: 34359655 PMCID: PMC8345071 DOI: 10.3390/cancers13153753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/21/2021] [Accepted: 07/23/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary The advent of DNA massive sequencing technologies has allowed for the first time an extensive look into the heterogeneous spectrum of genes and mutations underpinning myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). In this review, we wish to explore the most recent advances and the rationale for the potential therapeutic interest of three main actors in myelo-leukemic transformation: transcription factors that govern myeloid differentiation; RNA splicing factors, which ensure proper mRNA maturation and whose mutations increase R-loops formation; and deubiquitinating enzymes, which contribute to genome stability in hematopoietic stem cells (HSCs). Abstract Myeloid neoplasms encompass a very heterogeneous family of diseases characterized by the failure of the molecular mechanisms that ensure a balanced equilibrium between hematopoietic stem cells (HSCs) self-renewal and the proper production of differentiated cells. The origin of the driver mutations leading to preleukemia can be traced back to HSC/progenitor cells. Many properties typical to normal HSCs are exploited by leukemic stem cells (LSCs) to their advantage, leading to the emergence of a clonal population that can eventually progress to leukemia with variable latency and evolution. In fact, different subclones might in turn develop from the original malignant clone through accumulation of additional mutations, increasing their competitive fitness. This process ultimately leads to a complex cancer architecture where a mosaic of cellular clones—each carrying a unique set of mutations—coexists. The repertoire of genes whose mutations contribute to the progression toward leukemogenesis is broad. It encompasses genes involved in different cellular processes, including transcriptional regulation, epigenetics (DNA and histones modifications), DNA damage signaling and repair, chromosome segregation and replication (cohesin complex), RNA splicing, and signal transduction. Among these many players, transcription factors, RNA splicing proteins, and deubiquitinating enzymes are emerging as potential targets for therapeutic intervention.
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Rafferty K, Archer KJ, Turner K, Brown R, Jackson-Cook C. Trisomy 21-associated increases in chromosomal instability are unmasked by comparing isogenic trisomic/disomic leukocytes from people with mosaic Down syndrome. PLoS One 2021; 16:e0254806. [PMID: 34283872 PMCID: PMC8291705 DOI: 10.1371/journal.pone.0254806] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022] Open
Abstract
Down syndrome, which results from a trisomic imbalance for chromosome 21, has been associated with 80+ phenotypic traits. However, the cellular changes that arise in somatic cells due to this aneuploid condition are not fully understood. The primary aim of this study was to determine if germline trisomy 21 is associated with an increase in spontaneous somatic cell chromosomal instability frequencies (SCINF). To achieve this aim, we quantified SCINF in people with mosaic Down syndrome using a cytokinesis-blocked micronucleus assay. By comparing values in their isogenic trisomic/disomic cells, we obtained a measure of differences in SCINF that are directly attributable to a trisomy 21 imbalance, since differential effects attributable to "background" genetic factors and environmental exposures could be eliminated. A cross-sectional assessment of 69 people with mosaic Down syndrome (ages 1 to 44; mean age of 12.84 years) showed a significantly higher frequency of micronuclei in their trisomic (0.37 ± 0.35 [mean ± standard deviation]) compared to disomic cells (0.18 ± 0.11)(P <0.0001). The daughter binucleates also showed significantly higher levels of abnormal patterns in the trisomic (1.68 ± 1.21) compared to disomic (0.35 ± 0.45) cells (P <0.0001). Moreover, a significant Age x Cell Type interaction was noted (P = 0.0113), indicating the relationship between age and SCINF differed between the trisomic and disomic cells. Similarly, a longitudinal assessment (mean time interval of 3.9 years; range of 2 to 6 years) of 18 participants showed a mean 1.63-fold increase in SCINF within individuals over time for their trisomic cells (P = 0.0186), compared to a 1.13-fold change in their disomic cells (P = 0.0464). In summary, these results showed a trisomy 21-associated, age-related increase in SCINF. They also underscore the strength of the isogenic mosaic Down syndrome model system for "unmasking" cellular changes arising from a trisomy 21 imbalance.
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Affiliation(s)
- Kelly Rafferty
- Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Kellie J. Archer
- Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, Ohio, United States of America
| | - Kristi Turner
- Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Ruth Brown
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Colleen Jackson-Cook
- Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, United States of America
- * E-mail:
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33
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Gažová I, Lefevre L, Bush SJ, Rojo R, Hume DA, Lengeling A, Summers KM. CRISPR-Cas9 Editing of Human Histone Deubiquitinase Gene USP16 in Human Monocytic Leukemia Cell Line THP-1. Front Cell Dev Biol 2021; 9:679544. [PMID: 34136489 PMCID: PMC8203323 DOI: 10.3389/fcell.2021.679544] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/27/2021] [Indexed: 12/14/2022] Open
Abstract
USP16 is a histone deubiquitinase which facilitates G2/M transition during the cell cycle, regulates DNA damage repair and contributes to inducible gene expression. We mutated the USP16 gene in a high differentiation clone of the acute monocytic leukemia cell line THP-1 using the CRISPR-Cas9 system and generated four homozygous knockout clones. All were able to proliferate and to differentiate in response to phorbol ester (PMA) treatment. One line was highly proliferative prior to PMA treatment and shut down proliferation upon differentiation, like wild type. Three clones showed sustained expression of the progenitor cell marker MYB, indicating that differentiation had not completely blocked proliferation in these clones. Network analysis of transcriptomic differences among wild type, heterozygotes and homozygotes showed clusters of genes that were up- or down-regulated after differentiation in all cell lines. Prior to PMA treatment, the homozygous clones had lower levels than wild type of genes relating to metabolism and mitochondria, including SRPRB, encoding an interaction partner of USP16. There was also apparent loss of interferon signaling. In contrast, a number of genes were up-regulated in the homozygous cells compared to wild type at baseline, including other deubiquitinases (USP12, BAP1, and MYSM1). However, three homozygotes failed to fully induce USP3 during differentiation. Other network clusters showed effects prior to or after differentiation in the homozygous clones. Thus the removal of USP16 affected the transcriptome of the cells, although all these lines were able to survive, which suggests that the functions attributed to USP16 may be redundant. Our analysis indicates that the leukemic line can adapt to the extreme selection pressure applied by the loss of USP16, and the harsh conditions of the gene editing and selection protocol, through different compensatory pathways. Similar selection pressures occur during the evolution of a cancer in vivo, and our results can be seen as a case study in leukemic cell adaptation. USP16 has been considered a target for cancer chemotherapy, but our results suggest that treatment would select for escape mutants that are resistant to USP16 inhibitors.
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Affiliation(s)
- Iveta Gažová
- The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom
| | - Lucas Lefevre
- The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom
| | - Stephen J Bush
- The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom
| | - Rocio Rojo
- The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom
| | - David A Hume
- Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia
| | - Andreas Lengeling
- The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom
| | - Kim M Summers
- The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom.,Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia
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34
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Mark KG, Rape M. Ubiquitin-dependent regulation of transcription in development and disease. EMBO Rep 2021; 22:e51078. [PMID: 33779035 DOI: 10.15252/embr.202051078] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 11/29/2020] [Accepted: 03/01/2021] [Indexed: 12/19/2022] Open
Abstract
Transcription is an elaborate process that is required to establish and maintain the identity of the more than two hundred cell types of a metazoan organism. Strict regulation of gene expression is therefore vital for tissue formation and homeostasis. An accumulating body of work found that ubiquitylation of histones, transcription factors, or RNA polymerase II is crucial for ensuring that transcription occurs at the right time and place during development. Here, we will review principles of ubiquitin-dependent control of gene expression and discuss how breakdown of these regulatory circuits leads to a wide array of human diseases.
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Affiliation(s)
- Kevin G Mark
- Department of Molecular Cell Biology, University of California at Berkeley, Berkeley, CA, USA
| | - Michael Rape
- Department of Molecular Cell Biology, University of California at Berkeley, Berkeley, CA, USA.,Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA
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35
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Yang Y, Li J, Geng Y. Exosomes derived from chronic lymphocytic leukaemia cells transfer miR-146a to induce the transition of mesenchymal stromal cells into cancer-associated fibroblasts. J Biochem 2021; 168:491-498. [PMID: 32770182 DOI: 10.1093/jb/mvaa064] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/11/2020] [Indexed: 12/31/2022] Open
Abstract
Chronic lymphocytic leukaemia (CLL) is the most prevalent leukaemia and remains incurable. Mesenchymal stem cells (MSCs) can promote tumour progression by differentiating into cancer-associated fibroblasts (CAFs). However, the mechanisms by which tumour cells induce the transition of MSCs to CAFs are still largely undefined. Exosomes can regulate recipient cellular function by mediating intracellular communication. This study aimed to investigate whether CLL cells regulate the transition of bone marrow-derived MSCs (BM-MSCs) to CAFs via exosomal miR-146a delivery. The exosomes were isolated from CLL cell line MEC-1 (CLL-Exo) and then co-cultured with BM-MSCs. The expression of α-smooth muscle actin (α-SMA) and fibroblast-activated protein (FAP) were determined by immunofluorescence, quantitative real-time polymerase chain reaction and western blot. A luciferase reporter assay was performed to verify whether ubiquitin-specific peptidase 16 (USP16) was a target of miR-146a. CLL-Exo treatment up-regulated miR-146a and down-regulated expression of CAF markers (α-SMA and FAP) and USP16. The inducing effect of CLL-Exo on CAF marker expression was compromised when miR-146a expression was inhibited in CLL-Exo. USP16 was confirmed as a direct target of miR-146a and USP16 overexpression in BM-MSCs abrogated the CLL-Exo-mediated up-regulation of CAF markers. Collectively, CLL-Exo delivered miR-146a into BM-MSCs where miR-146a mediated transition of BM-MSCs into CAFs by targeting USP16.
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Affiliation(s)
- Yanli Yang
- Department of Hematology, The First Affiliated Hospital of Bengbu Medical College, No. 287 Changhuai Road, Bengbu 233004, Anhui Province, China
| | - Jun Li
- Department of Hematology, The First Affiliated Hospital of Bengbu Medical College, No. 287 Changhuai Road, Bengbu 233004, Anhui Province, China
| | - Yinghua Geng
- Department of Hematology, The First Affiliated Hospital of Bengbu Medical College, No. 287 Changhuai Road, Bengbu 233004, Anhui Province, China
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36
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Lanzillotta C, Di Domenico F. Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules. Biomolecules 2021; 11:biom11020266. [PMID: 33670211 PMCID: PMC7916967 DOI: 10.3390/biom11020266] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 12/11/2022] Open
Abstract
Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis. Increasing evidence has recently shown that oxidative stress (OS), associated with mitochondrial dysfunction and with the failure of antioxidant responses (e.g., SOD1 and Nrf2), is an early signature of DS, promoting protein oxidation and the formation of toxic protein aggregates. In turn, systems involved in the surveillance of protein synthesis/folding/degradation mechanisms, such as the integrated stress response (ISR), the unfolded stress response (UPR), and autophagy, are impaired in DS, thus exacerbating brain damage. A number of pre-clinical and clinical studies have been applied to the context of DS with the aim of rescuing redox balance and proteostasis by boosting the antioxidant response and/or inducing the mechanisms of protein re-folding and clearance, and at final of reducing cognitive decline. So far, such therapeutic approaches demonstrated their efficacy in reverting several aspects of DS phenotype in murine models, however, additional studies aimed to translate these approaches in clinical practice are still needed.
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37
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Basar MA, Beck DB, Werner A. Deubiquitylases in developmental ubiquitin signaling and congenital diseases. Cell Death Differ 2021; 28:538-556. [PMID: 33335288 PMCID: PMC7862630 DOI: 10.1038/s41418-020-00697-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023] Open
Abstract
Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate's stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have identified mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs.
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Affiliation(s)
- Mohammed A Basar
- Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA
| | - David B Beck
- Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA
- Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Achim Werner
- Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA.
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38
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Deubiquitylating enzymes in neuronal health and disease. Cell Death Dis 2021; 12:120. [PMID: 33483467 PMCID: PMC7822931 DOI: 10.1038/s41419-020-03361-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/11/2022]
Abstract
Ubiquitylation and deubiquitylation play a pivotal role in protein homeostasis (proteostasis). Proteostasis shapes the proteome landscape in the human brain and its impairment is linked to neurodevelopmental and neurodegenerative disorders. Here we discuss the emerging roles of deubiquitylating enzymes in neuronal function and survival. We provide an updated perspective on the genetics, physiology, structure, and function of deubiquitylases in neuronal health and disease. ![]()
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39
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MicroRNA regulation of cancer stem cells in the pathogenesis of breast cancer. Cancer Cell Int 2021; 21:31. [PMID: 33413418 PMCID: PMC7792222 DOI: 10.1186/s12935-020-01716-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 12/07/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is the most common cancer among women and accounts for 30% of all female malignancies worldwide. Breast cancer stem cells (BCSCs) are a small population of breast cancer cells that exhibit multiple characteristics including differentiation capacity, self-renewal and therapeutic resistance. Recently, BCSCs have attracted attention due to their modulation of breast tumor behaviors and drug resistance. miRNAs are small noncoding mRNAs involved in virtually all biological processes, including stem cell development, maintenance and differentiation. In breast cancer, miRNAs appear to be multi-faceted since they can act as either suppressors or oncogenes to regulate breast cancer progression. This review summarizes the critical roles of miRNAs in regulating multiple signaling pathways such as Wnt/β-catenin, Notch, PI3K/AKT/mTOR, BMI-1 and STAT3 that are important for the BCSC maintenance.
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40
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Yu JS, Huang T, Zhang Y, Mao XT, Huang LJ, Li YN, Wu TT, Zhong JY, Cao Q, Li YY, Jin J. Substrate-specific recognition of IKKs mediated by USP16 facilitates autoimmune inflammation. SCIENCE ADVANCES 2021; 7:7/3/eabc4009. [PMID: 33523871 PMCID: PMC7806237 DOI: 10.1126/sciadv.abc4009] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 10/22/2020] [Indexed: 05/11/2023]
Abstract
The classic NF-κB pathway plays crucial roles in various immune responses and inflammatory diseases. Its key kinase, IKKβ, participates in a variety of pathological and physiological processes by selectively recognizing its downstream substrates, including p105, p65, and IκBα, but the specific mechanisms of these substrates are unclear. Hyperactivation of one of the substrates, p105, is closely related to the onset of inflammatory bowel disease (IBD) in Nfkb1-deficient mice. In this study, we found that IKKβ ubiquitination on lysine-238 was substantially increased during inflammation. Using mass spectrometry, we identified USP16 as an essential regulator of the IKKβ ubiquitination level that selectively affected p105 phosphorylation without directly affecting p65 or IκBα phosphorylation. Furthermore, USP16 was highly expressed in colon macrophages in patients with IBD, and myeloid-conditional USP16-knockout mice exhibited reduced IBD severity. Our study provides a new theoretical basis for IBD pathogenesis and targeted precision intervention therapy.
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Affiliation(s)
- Jian-Shuai Yu
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Tao Huang
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Yu Zhang
- Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Xin-Tao Mao
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Ling-Jie Huang
- Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Yi-Ning Li
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Ting-Ting Wu
- Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Jiang-Yan Zhong
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Qian Cao
- Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016, China
| | - Yi-Yuan Li
- Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China.
| | - Jin Jin
- MOE Laboratory of Biosystem Homeostasis and Protection and Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
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41
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van den Berk P, Lancini C, Company C, Serresi M, Sanchez-Bailon MP, Hulsman D, Pritchard C, Song JY, Schmitt MJ, Tanger E, Popp O, Mertins P, Huijbers IJ, Jacobs H, van Lohuizen M, Gargiulo G, Citterio E. USP15 Deubiquitinase Safeguards Hematopoiesis and Genome Integrity in Hematopoietic Stem Cells and Leukemia Cells. Cell Rep 2020; 33:108533. [PMID: 33378683 PMCID: PMC7788286 DOI: 10.1016/j.celrep.2020.108533] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 07/28/2020] [Accepted: 11/25/2020] [Indexed: 12/22/2022] Open
Abstract
Altering ubiquitination by disruption of deubiquitinating enzymes (DUBs) affects hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. Here, we systematically inactivate DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNA (shRNA) screens. We find that multiple DUBs may be individually required for hematopoiesis and identify ubiquitin-specific protease 15 (USP15) as essential for HSC maintenance in vitro and in transplantations and Usp15 knockout (KO) mice in vivo. USP15 is highly expressed in human hematopoietic tissues and leukemias. USP15 depletion in murine progenitors and leukemia cells impairs in vitro expansion and increases genotoxic stress. In leukemia cells, USP15 interacts with and stabilizes FUS (fused in sarcoma), a known DNA repair factor, directly linking USP15 to the DNA damage response (DDR). Our study underscores the importance of DUBs in preserving normal hematopoiesis and uncovers USP15 as a critical DUB in safeguarding genome integrity in HSCs and leukemia cells.
In vivo shRNAs screens for deubiquitinases identify regulators of murine hematopoiesis Usp15 deletion compromises HSC maintenance and reconstitution potential in vivo USP15 loss affects genome integrity and growth of mHSPCs and human leukemia cells In human leukemia cells, USP15 stabilizes its interactor, FUS, a DNA repair factor
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Affiliation(s)
- Paul van den Berk
- Division of Tumor Biology and Immunology, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands
| | - Cesare Lancini
- Division of Molecular Genetics, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands
| | - Carlos Company
- Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13092 Berlin, Germany
| | - Michela Serresi
- Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13092 Berlin, Germany
| | | | - Danielle Hulsman
- Division of Molecular Genetics, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands; ONCODE Institute, Utrecht, the Netherlands
| | - Colin Pritchard
- Transgenic Core Facility, Mouse Clinic for Cancer and Aging (MCCA), the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands
| | - Ji-Ying Song
- Division of Experimental Animal Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands
| | - Matthias Jürgen Schmitt
- Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13092 Berlin, Germany
| | - Ellen Tanger
- Division of Molecular Genetics, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands
| | - Oliver Popp
- Proteomics Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Berlin Institute of Health, Robert Rössle Strasse 10, 13125 Berlin, Germany
| | - Philipp Mertins
- Proteomics Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Berlin Institute of Health, Robert Rössle Strasse 10, 13125 Berlin, Germany
| | - Ivo J Huijbers
- Transgenic Core Facility, Mouse Clinic for Cancer and Aging (MCCA), the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands
| | - Heinz Jacobs
- Division of Tumor Biology and Immunology, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands
| | - Maarten van Lohuizen
- Division of Molecular Genetics, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands; ONCODE Institute, Utrecht, the Netherlands
| | - Gaetano Gargiulo
- Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13092 Berlin, Germany.
| | - Elisabetta Citterio
- Division of Molecular Genetics, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands; ONCODE Institute, Utrecht, the Netherlands.
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Martínez-Cué C, Rueda N. Signalling Pathways Implicated in Alzheimer's Disease Neurodegeneration in Individuals with and without Down Syndrome. Int J Mol Sci 2020; 21:E6906. [PMID: 32962300 PMCID: PMC7555886 DOI: 10.3390/ijms21186906] [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] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 02/07/2023] Open
Abstract
Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer's disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.
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Affiliation(s)
- Carmen Martínez-Cué
- Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, 39011 Santander, Spain;
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Folci A, Mirabella F, Fossati M. Ubiquitin and Ubiquitin-Like Proteins in the Critical Equilibrium between Synapse Physiology and Intellectual Disability. eNeuro 2020; 7:ENEURO.0137-20.2020. [PMID: 32719102 PMCID: PMC7544190 DOI: 10.1523/eneuro.0137-20.2020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/08/2020] [Accepted: 06/17/2020] [Indexed: 01/04/2023] Open
Abstract
Posttranslational modifications (PTMs) represent a dynamic regulatory system that precisely modulates the functional organization of synapses. PTMs consist in target modifications by small chemical moieties or conjugation of lipids, sugars or polypeptides. Among them, ubiquitin and a large family of ubiquitin-like proteins (UBLs) share several features such as the structure of the small protein modifiers, the enzymatic cascades mediating the conjugation process, and the targeted aminoacidic residue. In the brain, ubiquitination and two UBLs, namely sumoylation and the recently discovered neddylation orchestrate fundamental processes including synapse formation, maturation and plasticity, and their alteration is thought to contribute to the development of neurological disorders. Remarkably, emerging evidence suggests that these pathways tightly interplay to modulate the function of several proteins that possess pivotal roles for brain homeostasis as well as failure of this crosstalk seems to be implicated in the development of brain pathologies. In this review, we outline the role of ubiquitination, sumoylation, neddylation, and their functional interplay in synapse physiology and discuss their implication in the molecular pathogenesis of intellectual disability (ID), a neurodevelopmental disorder that is frequently comorbid with a wide spectrum of brain pathologies. Finally, we propose a few outlooks that might contribute to better understand the complexity of these regulatory systems in regard to neuronal circuit pathophysiology.
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Affiliation(s)
- Alessandra Folci
- Humanitas Clinical and Research Center-IRCCS, via Manzoni 56, 20089, Rozzano (MI), Italy
| | - Filippo Mirabella
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve 9 Emanuele - Milan, Italy
| | - Matteo Fossati
- Humanitas Clinical and Research Center-IRCCS, via Manzoni 56, 20089, Rozzano (MI), Italy
- CNR-Institute of Neuroscience, via Manzoni 56, 20089, Rozzano (MI), Italy
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Rueda Revilla N, Martínez-Cué C. Antioxidants in Down Syndrome: From Preclinical Studies to Clinical Trials. Antioxidants (Basel) 2020; 9:antiox9080692. [PMID: 32756318 PMCID: PMC7464577 DOI: 10.3390/antiox9080692] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/16/2020] [Accepted: 07/23/2020] [Indexed: 12/16/2022] Open
Abstract
There is currently no effective pharmacological therapy to improve the cognitive dysfunction of individuals with Down syndrome (DS). Due to the overexpression of several chromosome 21 genes, cellular and systemic oxidative stress (OS) is one of the most important neuropathological processes that contributes to the cognitive deficits and multiple neuronal alterations in DS. In this condition, OS is an early event that negatively affects brain development, which is also aggravated in later life stages, contributing to neurodegeneration, accelerated aging, and the development of Alzheimer's disease neuropathology. Thus, therapeutic interventions that reduce OS have been proposed as a promising strategy to avoid neurodegeneration and to improve cognition in DS patients. Several antioxidant molecules have been proven to be effective in preclinical studies; however, clinical trials have failed to show evidence of the efficacy of different antioxidants to improve cognitive deficits in individuals with DS. In this review we summarize preclinical studies of cell cultures and mouse models, as well as clinical studies in which the effect of therapies which reduce oxidative stress and mitochondrial alterations on the cognitive dysfunction associated with DS have been assessed.
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Down syndrome, accelerated aging and immunosenescence. Semin Immunopathol 2020; 42:635-645. [PMID: 32705346 PMCID: PMC7666319 DOI: 10.1007/s00281-020-00804-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 06/29/2020] [Indexed: 12/11/2022]
Abstract
Down syndrome is the most common chromosomal disorder, associated with moderate to severe intellectual disability. While life expectancy of Down syndrome population has greatly increased over the last decades, mortality rates are still high and subjects are facing prematurely a phenomenon of atypical and accelerated aging. The presence of an immune impairment in Down syndrome subjects is suggested for a long time by the existence of an increased incidence of infections, the incomplete efficacy of vaccinations, and a high prevalence of autoimmunity. Immunologic abnormalities have been described since many years in this population, both from a numerical and a functional points of view, and these abnormalities can mirror the ones observed during normal aging. In this review, we summarize our knowledge on immunologic disturbances commonly observed in subjects with Down syndrome, and in innate and adaptive immunity, as well as regarding chronic inflammation. We then discuss the role of accelerated aging in these observed abnormalities and finally review the potential age-associated molecular and cellular mechanisms involved.
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Rozhok AI, Silberman RE, Higa KC, Liggett LA, Amon A, DeGregori J. A somatic evolutionary model of the dynamics of aneuploid cells during hematopoietic reconstitution. Sci Rep 2020; 10:12198. [PMID: 32699207 PMCID: PMC7376010 DOI: 10.1038/s41598-020-68729-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 04/28/2020] [Indexed: 11/28/2022] Open
Abstract
Aneuploidy is a feature of many cancers. Recent studies demonstrate that in the hematopoietic stem and progenitor cell (HSPC) compartment aneuploid cells have reduced fitness and are efficiently purged from the bone marrow. However, early phases of hematopoietic reconstitution following bone marrow transplantation provide a window of opportunity whereby aneuploid cells rise in frequency, only to decline to basal levels thereafter. Here we demonstrate by Monte Carlo modeling that two mechanisms could underlie this aneuploidy peak: rapid expansion of the engrafted HSPC population and bone marrow microenvironment degradation caused by pre-transplantation radiation treatment. Both mechanisms reduce the strength of purifying selection acting in early post-transplantation bone marrow. We explore the contribution of other factors such as alterations in cell division rates that affect the strength of purifying selection, the balance of drift and selection imposed by the HSPC population size, and the mutation-selection balance dependent on the rate of aneuploidy generation per cell division. We propose a somatic evolutionary model for the dynamics of cells with aneuploidy or other fitness-reducing mutations during hematopoietic reconstitution following bone marrow transplantation. Similar alterations in the strength of purifying selection during cancer development could help explain the paradox of aneuploidy abundance in tumors despite somatic fitness costs.
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Affiliation(s)
- Andrii I Rozhok
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
| | - Rebecca E Silberman
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.,Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.,Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Kelly C Higa
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.,Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - L Alex Liggett
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Angelika Amon
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.,Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.,Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - James DeGregori
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. .,Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. .,Department of Pediatrics, Section of Pediatric Hematology/Oncology/BMT, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. .,Department of Medicine, Section of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
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Regulation of Histone Ubiquitination in Response to DNA Double Strand Breaks. Cells 2020; 9:cells9071699. [PMID: 32708614 PMCID: PMC7407225 DOI: 10.3390/cells9071699] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/10/2020] [Accepted: 07/14/2020] [Indexed: 12/11/2022] Open
Abstract
Eukaryotic cells are constantly exposed to both endogenous and exogenous stressors that promote the induction of DNA damage. Of this damage, double strand breaks (DSBs) are the most lethal and must be efficiently repaired in order to maintain genomic integrity. Repair of DSBs occurs primarily through one of two major pathways: non-homologous end joining (NHEJ) or homologous recombination (HR). The choice between these pathways is in part regulated by histone post-translational modifications (PTMs) including ubiquitination. Ubiquitinated histones not only influence transcription and chromatin architecture at sites neighboring DSBs but serve as critical recruitment platforms for repair machinery as well. The reversal of these modifications by deubiquitinating enzymes (DUBs) is increasingly being recognized in a number of cellular processes including DSB repair. In this context, DUBs ensure proper levels of ubiquitin, regulate recruitment of downstream effectors, dictate repair pathway choice, and facilitate appropriate termination of the repair response. This review outlines the current understanding of histone ubiquitination in response to DSBs, followed by a comprehensive overview of the DUBs that catalyze the removal of these marks.
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Wen Y, He H, Liu H, An Q, Wang D, Ding X, Shi Q, Feng Y, Wang E, Lei C, Zhang Z, Huang Y. Copy number variation of the USP16 gene and its association with milk traits in Chinese Holstein cattle. Anim Biotechnol 2020; 33:98-103. [PMID: 32646283 DOI: 10.1080/10495398.2020.1777148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Copy number variations (CNVs) were similar to single nucleotide polymorphisms (SNPs) and insertion-deletion (InDel), regarded as genetic variations in many species. CNV is defined as the variable change of DNA segment length compared with the reference genome, including gains or losses from 50 bp to several mega bases. The functions of USP16 gene are diverse, such as regulating the cell cycle, DNA damage, histone H2A deubiquitination or mitotic nuclear division. To analyze the relationship between CNV of USP16 gene and milk traits in Chinese Holstein, we used qPCR to detect the individuals of Chinese Holstein (n = 180). The results showed that the effect of USP16 gene CNV on daily milk yield and fat percentage had significant difference (p < 0.05). The gain was the advantage type in daily milk yield and the loss was the advantage type in fat percentage. Therefore, CNV of USP16 gene is an important factor of milk traits in Chinese Holstein. Meanwhile, it may be used as a molecular marker for assisted selection of milk traits in Chinese Holstein, which provides a theoretical basis for the genetic improvement of cow breeds in China.
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Affiliation(s)
- Yifan Wen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Hua He
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Hongbing Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Qingming An
- College of Agriculture and Forestry Engineering, Tongren Unviersity, Tongren, Guizhou, People's Republic of China
| | - Dahui Wang
- College of Agriculture and Forestry Engineering, Tongren Unviersity, Tongren, Guizhou, People's Republic of China
| | - Xiaoting Ding
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Qiaoting Shi
- Henan Academy of Agricultural Sciences, Institute of Animal Husbandry and Veterinary Science, Zhengzhou, Henan, People's Republic of China
| | - Yajie Feng
- Henan Academy of Agricultural Sciences, Institute of Animal Husbandry and Veterinary Science, Zhengzhou, Henan, People's Republic of China
| | - Eryao Wang
- Henan Academy of Agricultural Sciences, Institute of Animal Husbandry and Veterinary Science, Zhengzhou, Henan, People's Republic of China
| | - Chuzhao Lei
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
| | - Zijing Zhang
- Henan Academy of Agricultural Sciences, Institute of Animal Husbandry and Veterinary Science, Zhengzhou, Henan, People's Republic of China
| | - Yongzhen Huang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China
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Ruan J, Schlüter D, Wang X. Deubiquitinating enzymes (DUBs): DoUBle-edged swords in CNS autoimmunity. J Neuroinflammation 2020; 17:102. [PMID: 32248814 PMCID: PMC7132956 DOI: 10.1186/s12974-020-01783-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 03/23/2020] [Indexed: 12/31/2022] Open
Abstract
Multiple sclerosis (MS) is the most common autoimmune disease of the CNS. The etiology of MS is still unclear but it is widely recognized that both genetic and environmental factors contribute to its pathogenesis. Immune signaling and responses are critically regulated by ubiquitination, a posttranslational modification that is promoted by ubiquitinating enzymes and inhibited by deubiquitinating enzymes (DUBs). Genome-wide association studies (GWASs) identified that polymorphisms in or in the vicinity of two human DUB genes TNFAIP3 and USP18 were associated with MS susceptibility. Studies with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, have provided biological rationale for the correlation between these DUBs and MS. Additional studies have shown that other DUBs are also involved in EAE by controlling distinct cell populations. Therefore, DUBs are emerging as crucial regulators of MS/EAE and might become potential therapeutic targets for the clinical treatment of MS.
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Affiliation(s)
- Jing Ruan
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Dirk Schlüter
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Carl-Neuberg-Straße-1, 30626, Hannover, Germany. .,Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, 30625, Hannover, Germany.
| | - Xu Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan High Education Park, Wenzhou, 325035, China.
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