Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease–linked transcription factor
- Zoe L. Grant
- Shuzhen Kuang
- Shu Zhang
- Abraham J. Horrillo
- Zhe Chen
- Kavitha S. Rao
- Cemre Celen
- Vasumathi Kameswaran
- Carine Joubran
- Pik Ki Lau
- Keyi Dong
- Bing Yang
- Weronika M. Bartosik
- Nathan R. Zemke
- Bing Ren
- Deepak Srivastava
- Irfan S. Kathiriya
- Katherine S. Pollard
- Benoit G. Bruneau
2026-07-23
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 three-dimensional (3D) chromatin during cellular differentiation. In this work, 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, was sensitive to reduced TBX5 dosage in a human model of CHD, with variations in response across individual cells. Cohesin binding was reduced at TBX5-bound enhancer elements in a TBX5 dose-dependent manner, 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 mechanism for TF-dependent disease.