{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T20:01:49Z","timestamp":1791576109861,"version":"4.3.4"},"reference-count":87,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"22","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2022,5,31]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>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\u2013throughput chromosome conformation capture, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and RNA sequencing. We used human induced pluripotent stem cell\u2013derived cardiomyocytes and mouse models to interrogate the key transcription factor implicated in 3-dimensional chromatin organization and transcriptional regulation in DCM pathogenesis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              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\n              <jats:italic>NPPA-AS1<\/jats:italic>\n              (natriuretic peptide A antisense RNA 1) promoter functions as an enhancer and physically interacts with the\n              <jats:italic>NPPA<\/jats:italic>\n              (natriuretic peptide A) and\n              <jats:italic>NPPB<\/jats:italic>\n              (natriuretic peptide B) promoters, leading to the cotranscription of\n              <jats:italic>NPPA<\/jats:italic>\n              and\n              <jats:italic>NPPB<\/jats:italic>\n              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\u2013promoter connectome in DCM hearts, we performed comprehensive 3-dimensional epigenome mappings in human induced pluripotent stem cell\u2013derived cardiomyocytes. We found that forced overexpression of\n              <jats:italic>HAND1<\/jats:italic>\n              in human induced pluripotent stem cell\u2013derived cardiomyocytes induced a distinct gain of enhancer\u2013promoter 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\n              <jats:italic>HAND1<\/jats:italic>\n              in human induced pluripotent stem cell\u2013derived cardiomyocytes induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of\n              <jats:italic>Hand1<\/jats:italic>\n              in the mouse hearts resulted in dilated cardiac remodeling with impaired contractility\/Ca\n              <jats:sup>2+<\/jats:sup>\n              handling in cardiomyocytes, increased ratio of heart weight\/body weight, and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>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\u2013promoter connectome to drive DCM pathogenesis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.121.055781","type":"journal-article","created":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T09:00:15Z","timestamp":1649667615000},"page":"1663-1683","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["Rewiring of 3D Chromatin Topology Orchestrates Transcriptional Reprogramming and the Development of Human Dilated Cardiomyopathy"],"prefix":"10.1161","volume":"145","author":[{"given":"Yuliang","family":"Feng","sequence":"first","affiliation":[{"name":"Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK (Y.F., F.L., S.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuyang","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, China (L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanzi","family":"Hong","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Geriatrics Institute, Guangdong Provincial People\u2019s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (W. Hong, N.T., Y.M., Q.G., Y.L., L.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China (C.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Tan","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Geriatrics Institute, Guangdong Provincial People\u2019s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (W. 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