Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease-linked transcription factor.
ZL, G., S, K., S, Z., AJ, H., Z, C., KS, R., C, C., V, K., C, J., & PK, L. (2026). Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease-linked transcription factor.. Science (New York, N.Y.). https://doi.org/10.1126/science.adv5434
ZL G, S K, S Z, AJ H, Z C, KS R, et al. Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease-linked transcription factor.. Science (New York, N.Y.). 2026; doi: 10.1126/science.adv5434
ZL G, S K, S Z, et al. Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease-linked transcription factor.[J]. Science (New York, N.Y.). 2026. DOI: 10.1126/science.adv5434.
@article{zl2026,
author = {Grant ZL and Kuang S and Zhang S and Horrillo AJ and Chen Z and Rao KS and Celen C and Kameswaran V and Joubran C and Lau PK},
title = {Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease-linked transcription factor.},
journal = {Science (New York, N.Y.)},
year = {2026},
doi = {10.1126/science.adv5434},
note = {PMID: 42490494},
}
TY - JOUR AU - Grant ZL AU - Kuang S AU - Zhang S AU - Horrillo AJ AU - Chen Z AU - Rao KS AU - Celen C AU - Kameswaran V AU - Joubran C AU - Lau PK TI - Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease-linked transcription factor. T2 - Science (New York, N.Y.) PY - 2026 DO - 10.1126/science.adv5434 AN - PMID:42490494 ER -
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.