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

Abstract

Dosage-sensitive transcription factors (TFs) underlie altered gene regulation in human developmental disorders, 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 are especially sensitive, while co-occupancy with CTCF partially protects 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.

Authors

Grant ZL  •  Kuang S  •  Zhang S  •  Horrillo AJ  •  Rao KS  •  Kameswaran V  •  Joubran C  •  Lau PK  •  Dong K  •  Yang B  •  Bartosik WM  •  Zemke NR  •  Ren B  •  Kathiriya IS  •  Pollard KS  •  Bruneau BG

Link

http://biorxiv.org/lookup/doi/10.1101/2025.01.09.632202