Dose-dependent sensitivity of human 3D chromatin to a heart disease-linked transcription factor [Hi-C]

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. Hi-C 3.0 of WTC11, cells from atrial cardiomyocyte differentation at D2, D4, D6, D11, D20 and D45, cells from ventricular cardiomyocyte differentation at D2, D4, D6, D11 and D23, cells from atrial cardiomyocyte differentation at D20 from WT (TBX5+/+), heterozygous (TBX5in/+) and null (TBX5in/del) WTC11