Yuliang Feng1, Liuyang Cai2, Wanzi Hong3, Chunxiang Zhang4, Ning Tan3, Mingyang Wang5, Cheng Wang6, Feng Liu1, Xiaohong Wang7, Jianyong Ma7, Chen Gao7, Mohit Kumar8,7, Yuanxi Mo3, Qingshan Geng3, Changjun Luo9, Yan Lin3, Haiyang Chen10, Shuang-Yin Wang11, Michael J Watson12, Anil G Jegga13,14,15, Roger A Pedersen16, Ji-Dong Fu17, Zhao V Wang18, Guo-Chang Fan7, Sakthivel Sadayappan8, Yigang Wang19, Siim Pauklin1, Feng Huang9, Wei Huang19, Lei Jiang3. 1. Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK (Y.F., F.L., S.P.). 2. Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, China (L.C.). 3. Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (W. Hong, N.T., Y.M., Q.G., Y.L., L.J.). 4. Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China (C.Z.). 5. College of Engineering and Applied Science (M.W.), University of Cincinnati, OH. 6. Smurfit Institute of Genetics, Trinity College Dublin, Ireland (C.W.). 7. Departments of Pharmacology and Systems Physiology (X.W., J.M., C.G., M.K., G.-C.F.), University of Cincinnati College of Medicine, OH. 8. Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease (M.K., S.S.), University of Cincinnati, OH. 9. Institute of Cardiovascular Diseases, the First Affiliated Hospital of Guangxi Medical University, Nanning, China (C.L., F.H.). 10. National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China (H.C.). 11. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel (S.-Y.W.). 12. Department of Surgery, Cardiovascular & Thoracic, Duke University, Durham, NC (M.J.W.). 13. Pediatrics (A.G.J.), University of Cincinnati College of Medicine, OH. 14. Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, OH (A.G.J.). 15. Department of Computer Science, University of Cincinnati College of Engineering, OH (A.G.J.). 16. Department of OB-GYN/Reproductive, Perinatal and Stem Cell Biology Research, Stanford University, CA (R.A.P.). 17. Departments of Physiology and Cell Biology, the Dorothy M. Davis Heart and Lung Research Institute, Frick Center for Heart Failure and Arrhythmia, the Ohio State University, Columbus (J.-d.F.). 18. Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas (Z.V.W.). 19. Pathology and Laboratory Medicine (Y.W., W. Huang), University of Cincinnati College of Medicine, OH.
Abstract
BACKGROUND: Transcriptional reconfiguration is central to heart failure, the most common cause of which is dilated cardiomyopathy (DCM). The effect of 3-dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive. METHODS: We generated a compendium of 3-dimensional epigenome and transcriptome maps from 101 biobanked human DCM and nonfailing heart tissues through highly integrative chromatin immunoprecipitation (H3K27ac [acetylation of lysine 27 on histone H3]), in situ high-throughput chromosome conformation capture, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and RNA sequencing. We used human induced pluripotent stem cell-derived cardiomyocytes and mouse models to interrogate the key transcription factor implicated in 3-dimensional chromatin organization and transcriptional regulation in DCM pathogenesis. RESULTS: We discovered that the active regulatory elements (H3K27ac peaks) and their connectome (H3K27ac loops) were extensively reprogrammed in DCM hearts and contributed to transcriptional dysregulation implicated in DCM development. For example, we identified that nontranscribing NPPA-AS1 (natriuretic peptide A antisense RNA 1) promoter functions as an enhancer and physically interacts with the NPPA (natriuretic peptide A) and NPPB (natriuretic peptide B) promoters, leading to the cotranscription of NPPA and NPPB in DCM hearts. We revealed that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (compartments, topologically associating domains) and their anchors unexpectedly had equivalent chromatin accessibility. We discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for HAND1 (heart and neural crest derivatives expressed 1), a key transcription factor involved in early cardiogenesis. In line with this, its protein expression was upregulated in human DCM and mouse failing hearts. To further validate whether HAND1 is a causal driver for the reprogramming of enhancer-promoter connectome in DCM hearts, we performed comprehensive 3-dimensional epigenome mappings in human induced pluripotent stem cell-derived cardiomyocytes. We found that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced a distinct gain of enhancer-promoter connectivity and correspondingly increased the expression of their connected genes implicated in DCM pathogenesis, thus recapitulating the transcriptional signature in human DCM hearts. Electrophysiology analysis demonstrated that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in dilated cardiac remodeling with impaired contractility/Ca2+ handling in cardiomyocytes, increased ratio of heart weight/body weight, and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM. CONCLUSIONS: This study provided novel chromatin topology insights into DCM pathogenesis and illustrated a model whereby a single transcription factor (HAND1) reprograms the genome-wide enhancer-promoter connectome to drive DCM pathogenesis.
BACKGROUND: Transcriptional reconfiguration is central to heart failure, the most common cause of which is dilated cardiomyopathy (DCM). The effect of 3-dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive. METHODS: We generated a compendium of 3-dimensional epigenome and transcriptome maps from 101 biobanked human DCM and nonfailing heart tissues through highly integrative chromatin immunoprecipitation (H3K27ac [acetylation of lysine 27 on histone H3]), in situ high-throughput chromosome conformation capture, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and RNA sequencing. We used human induced pluripotent stem cell-derived cardiomyocytes and mouse models to interrogate the key transcription factor implicated in 3-dimensional chromatin organization and transcriptional regulation in DCM pathogenesis. RESULTS: We discovered that the active regulatory elements (H3K27ac peaks) and their connectome (H3K27ac loops) were extensively reprogrammed in DCM hearts and contributed to transcriptional dysregulation implicated in DCM development. For example, we identified that nontranscribing NPPA-AS1 (natriuretic peptide A antisense RNA 1) promoter functions as an enhancer and physically interacts with the NPPA (natriuretic peptide A) and NPPB (natriuretic peptide B) promoters, leading to the cotranscription of NPPA and NPPB in DCM hearts. We revealed that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (compartments, topologically associating domains) and their anchors unexpectedly had equivalent chromatin accessibility. We discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for HAND1 (heart and neural crest derivatives expressed 1), a key transcription factor involved in early cardiogenesis. In line with this, its protein expression was upregulated in human DCM and mouse failing hearts. To further validate whether HAND1 is a causal driver for the reprogramming of enhancer-promoter connectome in DCM hearts, we performed comprehensive 3-dimensional epigenome mappings in human induced pluripotent stem cell-derived cardiomyocytes. We found that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced a distinct gain of enhancer-promoter connectivity and correspondingly increased the expression of their connected genes implicated in DCM pathogenesis, thus recapitulating the transcriptional signature in human DCM hearts. Electrophysiology analysis demonstrated that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in dilated cardiac remodeling with impaired contractility/Ca2+ handling in cardiomyocytes, increased ratio of heart weight/body weight, and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM. CONCLUSIONS: This study provided novel chromatin topology insights into DCM pathogenesis and illustrated a model whereby a single transcription factor (HAND1) reprograms the genome-wide enhancer-promoter connectome to drive DCM pathogenesis.
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