Dose-dependent sensitivity of human 3D chromatin to a heart disease-linked transcription factor [RNA-Seq 2]

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. Cohesin binding was dose-dependently reduced at TBX5-bound enhancer elements in the absence of TBX5, providing a potential mechanism for disrupted loop formation. 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.