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

Grant, Z. L.; Kuang, S.; Zhang, S.; Horrillo, A. J.; Rao, K. S.; Kameswaran, V.; Joubran, C.; Lau, P. K.; Dong, K.; Yang, B.; Bartosik, W. M.; Zemke, N. R.; Ren, B.; Kathiriya, I. S.; Pollard, K. S.; Bruneau, B. G.

doi:10.1101/2025.01.09.632202

bioRxiv · 10.1101/2025.01.09.632202

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

Grant, Z. L.·Kuang, S.·Zhang, S.·Horrillo, A. J.·Rao, K. S.·Kameswaran, V.·Joubran, C.·Lau, P. K.·Dong, K.·Yang, B.·Bartosik, W. M.·Zemke, N. R.·Ren, B.·Kathiriya, I. S.·Pollard, K. S.·Bruneau, B. G.

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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.

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Grant, Z. L., Kuang, S., Zhang, S., Horrillo, A. J., Rao, K. S., Kameswaran, V., Joubran, C., Lau, P. K., Dong, K., Yang, B., Bartosik, W. M., Zemke, N. R., Ren, B., Kathiriya, I. S., Pollard, K. S., Bruneau, B. G.. 2025-01-12. Dose-dependent sensitivity of human 3D chromatin to a heart disease-linked transcription factor. https://doi.org/10.1101/2025.01.09.632202

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