EXPERIMENT_TITLE: Hi-C of Homo sapiens: atrial cardiomyocyte differentiation at D20 from WTC11 with TBX5in/del rep2
STUDY_DESCRIPTOR_STUDY_ABSTRACT: Dosage-sensitive transcription factors (TFs) underlie altered gene regulation in congenital heart disease (CHD), and cell-type specific gene regulation is linked to the reorganization of 3D chromatin during cellular differentiation. Here, we show dose-dependent regulation of chromatin organization by the congenital heart disease (CHD)-linked, lineage-restricted TF TBX5 in human cardiomyocyte differentiation. Genome organization, including compartments, topologically associated domains, and chromatin loops, are sensitive to reduced TBX5 dosage in a human model of CHD, with variations in response across individual cells. Regions normally bound by TBX5 were especially sensitive, while co-occupancy with CTCF partially protected TBX5-bound TAD boundaries and loop anchors. These results highlight the importance of lineage-restricted TF dosage in cell-type specific 3D chromatin dynamics, suggesting a new mechanism for TF-dependent disease.
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