机构：[1]Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Old Road, Headington, Oxford, UK.[2]Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.[3]Guangdong Provincial Geriatrics Institute, Guangdong Provincial People 's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.[4]Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.[5]College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH.[6]Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.[7]Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH.[8]Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, OH.[9]Institute of Cardiovascular Diseases, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.[10]National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.四川大学华西医院[11]Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.[12]Department of Surgery, Cardiovascular and Thoracic, Duke University, Durham, NC.[13]Division of Biomedical Informatics, Cincinnati Children 's Hospital Medical Center, Cincinnati, OH[14]Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH[15]Department of Computer Science, University of Cincinnati College of Engineering, Cincinnati, OH[16]Department of OB-GYN/Reproductive, Perinatal and Stem Cell Biology Research, Stanford University, Stanford, CA[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, OH[18]Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX[19]Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH
Background: Transcriptional reconfiguration is central to heart failure, the common cause of which is dilated cardiomyopathy (DCM). However, the impact of three-dimensional (3D) chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive. Methods: We generated a compendium of 3D-epigenome and transcriptome maps from 101 biobanked human DCM and non-failing heart tissues through HiChIP (H3K27ac), in situ Hi-C, ChIP-seq, ATAC-seq and RNA-seq profiling. We employed human iPSC-derived cardiomyocytes (hiPSC-CMs) and mouse models to further interrogate the key transcription factor implicated in 3D 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 for DCM development. For example, we identified that non-transcribing NPPA-AS1 promoter functions as an enhancer and physically interacts with the NPPA and NPPB promoters, leading to the co-transcription of NPPA and NPPB in DCM hearts. We uncovered that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (Compartments, Topologically Associating Domains) and unexpectedly their anchors had equivalent chromatin accessibility. Intriguingly, we discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for Heart and Neural Crest Derivatives Expressed 1 (HAND1), 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 3D epigenome mappings in hiPSC-CMs. We found that forced overexpression of HAND1 in hiPSC-CM induced a distinct gain of enhancer/promoter connectivity and, correspondingly, increased the expression of their connected genes implicated in DCM etiology, thus recapitulating the transcriptional signature in human DCM hearts. Moreover, electrophysiology analysis demonstrated that forced overexpression of HAND1 in hiPSC-CM induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in a 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.
基金：
National Natural Science Foundation of China (No.81800262 to
L.J.; 81670334 to N.T; 81560046 and 81760057 to F.H.; 81670398 and 91639102 to C.X.Z.;
31622031, 31671254, and 91749110 to H.C, Natural Science Foundation of Guangdong Province (No.2018A030313029 to L.J.), Science and Technology Planning Project of
Guangzhou (No.201903010005 to L.J.), High-level Hospital Construction Project of Guangdong
Province (DFJH201909 to N.T.). National Institutes of Health (NIH) grants R01HL160811 and
GM-132149 (to G-C.F.), NIH grants R01HL143490 and R01HL136025, R01 HL157456 (to
Y.W.), NIH grants R01HL139006 (to J.F.). American Heart Association (AHA) Career
Development Award (20CDA35310176 to W. H.), AHA Career Development Award
(19CDA34630009 to C. G.), AHA Postdoctoral Fellowship (834316 to M. K.). Clarendon Fund
and St. Edmund Hall Scholarship SFF1920_CB_MSD_759707, to Y.F.) and Cancer Research
UK Career Development Fellowship (C59392/A25064 to S.P.). Dr. Sadayappan has received
support from National Institutes of Health grants R01 AR078001, R01 HL130356, R01
HL105826, R38 HL155775 and R01 HL143490. This work was further supported by the AHA
2019 Institutional Undergraduate Student (19UFEL34380251) and Transformation
(19TPA34830084) awards, the PLN Foundation (PLN crazy idea) and the Leducq Foundation
(Transatlantic Network 18CVD01, PLN-CURE).
第一作者机构：[1]Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Old Road, Headington, Oxford, UK.[*1]Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Old Road, Headington, Oxford, UK
共同第一作者：
通讯作者：
通讯机构：[1]Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Old Road, Headington, Oxford, UK.[3]Guangdong Provincial Geriatrics Institute, Guangdong Provincial People 's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.[9]Institute of Cardiovascular Diseases, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.[19]Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH[*1]Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Old Road, Headington, Oxford, UK[*2]Institute of Cardiovascular Diseases, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China[*3]Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH[*4]Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
推荐引用方式(GB/T 7714)：
Feng Yuliang,Cai Liuyang,Hong Wanzi,et al.Rewiring of 3D Chromatin Topology Orchestrates Transcriptional Reprogramming and the Development of Human Dilated Cardiomyopathy.[J].CIRCULATION.2022,145(22):1663-1683.doi:10.1161/CIRCULATIONAHA.121.055781.
APA：
Feng Yuliang,Cai Liuyang,Hong Wanzi,Zhang Chunxiang,Tan Ning...&Jiang Lei.(2022).Rewiring of 3D Chromatin Topology Orchestrates Transcriptional Reprogramming and the Development of Human Dilated Cardiomyopathy..CIRCULATION,145,(22)
MLA：
Feng Yuliang,et al."Rewiring of 3D Chromatin Topology Orchestrates Transcriptional Reprogramming and the Development of Human Dilated Cardiomyopathy.".CIRCULATION 145..22(2022):1663-1683
医学