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Reprogramming of three-dimensional chromatin architecture drives human dilated cardiomyopathy

ABSTRACT: Here we generated the first reference 3D chromatin contact maps from 101 biobanked human heart tissue samples through HiChIP (H3K27ac), in situ Hi-C, ChIP-seq, ATAC-seq and RNA-seq profiling. We discovered that the active regulatory elements and their connectome were extensively reprogrammed in DCM and contributed to transcription dysregulation implicated for DCM development. Higher-order chromatin structures indicated that the overall genome architecture was largely invariant in DCM and chromatin accessibility did not alter DCM-specific H3K27ac loops. This provided insight to the mechanistic hierarchies between higher-order chromatin structures, cis-regulatory elements and differential chromatin accessibilities in DCM, suggesting the importance of sequence-specific transcription factors. Intriguingly, we uncovered that the DCM-specific H3K27ac loops 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 hearts and mouse failing hearts. Functional analyses by ectopic overexpression of HAND1 in human iPSC-derived cardiomyocytes induced cell hypertrophy and abnormal electrophysiology. Moreover, cardiomyocyte-specific overexpression of HAND1 in the mouse heart resulted in cardiomyocyte enlargement, increased heart weight/body weight ratio and dilated left ventricle. Echocardiography showed that cardiomyocyte-specific Hand1 overexpression in the mouse heart led to cardiac dysfunction and remodeling. Thus, aberrant activation of HAND1 in adult cardiomyocytes recapitulated the phenotypes observed in human DCM and indicated the involvement of a partial reactivation of a developmentally earlier cell identity program in the disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165303 | GEO | 2022/05/13

REPOSITORIES: GEO

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Project description:Background: Modulation of mRNA splicing acts as an important layer of gene regulation, in addition to transcriptional regulation and epigenetic modifications. RNA binding proteins (RBPs) play essential roles in mediating RNA splicing and are key regulators of heart development and function. Our previous studies demonstrated that RBPMS (RNA-binding protein with multiple splicing) regulates cardiac development through modulating mRNA splicing during embryogenesis. Here we explored the postnatal function of RBPMS in the heart. Methods: We ablated Rbpms in the heart by generating a cardiac-specific knockout mouse line (Myh6-Cre, Rbpmsfl/fl), and evaluated its cardiac functions by histology, echocardiography, and gene expression. Paired-end RNA sequencing and RT-PCR were performed to identify and validate splicing targets of RBPMS in adult mouse hearts. Proximity-dependent Biotin Identification (BioID) assay and mass spectrometry analysis were performed to identify RBPMS binding partners. We also measured contractility and calcium fluxes in isolated mouse cardiomyocytes, and contractile forces of cardiac papillary muscle. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) were also used as a model to explore the influence of RBPMS on contractility of human cardiomyocytes. Results: he absence of Rbpms in the heart led to dilated cardiomyopathy (DCM) and heart failure, causing early death in mice. Mice with cardiac-specific knockout of Rbpms showed myocardium noncompaction with reduced cardiomyocyte number at the neonatal stage and developed DCM with pervasive myocardial fibrosis in adulthood. We found that RBPMS mediates a largely distinct RNA splicing profile in adult mouse hearts compared to neonatal hearts, indicating a stage-specific modulation of alternative RNA splicing by RBPMS. In adult hearts, RBPMS mainly influenced alternative splicing of genes associated with sarcomere structures and cardiomyocyte contraction, such as Ttn, Pdlim5 and Nexn, to generate new protein isoforms. In neonatal hearts, RBPMS influenced the splicing of cytoskeletal genes. RBMPS was associated with spliceosome factors and other RNA binding proteins that play important roles in the heart, such as RBM20 and GATA4. Importantly, we found that the absence of Rbpms caused severe cardiomyocyte contractile defects and reduced calcium sensitivity in both mouse and hiPSC-CMs. Our results demonstrated that Rbpms is crucial for postnatal cardiac function and cardiomyocyte contractility by regulating RNA alternative splicing. Conclusions: Loss of Rbpms in the heart causes reduced cardiomyocyte number and impaired cardiomyocyte contraction, leading to DCM and heart failure.

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Reprogramming of three-dimensional chromatin architecture drives human dilated cardiomyopathy

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