EXPERIMENT_TITLE: GSM5029739: DCM-1_HiC; Homo sapiens; Hi-C
EXPERIMENT_DESIGN_LIBRARY_DESCRIPTOR_LIBRARY_CONSTRUCTION_PROTOC: In situ Hi-C: In situ HiC was performed in a similar way as HiChIP with the exception of chromatin immunoprecipitation being performed using the H3K27ac antibody and protein A beads.
STUDY_DESCRIPTOR_STUDY_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. Overall design: H3K27ac HiChIP, In-situ Hi-C, H3K27ac ChIP-seq, HAND1 ChIP-seq, ATAC-seq, RNA-seq for human non-failing and failing (DCM) heart tissues. H3K27ac HiChIP, H3K27ac ChIP-seq, HAND1 ChIP-seq, RNA-seq for human iPSC-derived cardiomyocytes.
SAMPLE_TITLE: DCM-1_HiC
SAMPLE_SAMPLE_ATTRIBUTES_SAMPLE_ATTRIBUTE: [{"TAG": "source_name", "VALUE": "heart tissue"}, {"TAG": "tissue", "VALUE": "heart"}, {"TAG": "method", "VALUE": "Hi-C"}, {"TAG": "factor", "VALUE": "NA"}, {"TAG": "condition", "VALUE": "dilated cardiomyopathy"}]
Pool_Member_@attributes_sample_title: DCM-1_HiC
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