Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease–linked transcription factor
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.
Authors
- Deepak Srivastava (ORCID: https://orcid.org/0000-0002-3480-5953)
- Benoit G. Bruneau (ORCID: https://orcid.org/0000-0002-0804-7597)
- Katherine S. Pollard (ORCID: https://orcid.org/0000-0002-9870-6196)
- Kavitha S. Rao (ORCID: https://orcid.org/0000-0001-5401-6989)
- Shuzhen Kuang (ORCID: https://orcid.org/0009-0008-3844-3647)
- Zoe L. Grant (ORCID: https://orcid.org/0000-0003-0580-5222)
- Cemre Celen (ORCID: https://orcid.org/0000-0001-8308-3750)
- Nathan R. Zemke (ORCID: https://orcid.org/0000-0002-6326-5925)
- Vasumathi Kameswaran (ORCID: https://orcid.org/0000-0003-2552-6183)
- Carine Joubran (ORCID: https://orcid.org/0000-0002-8747-6954)
- Bing Ren (ORCID: https://orcid.org/0000-0002-5435-1127)
- Irfan S. Kathiriya (ORCID: https://orcid.org/0000-0003-1207-1490)
- Pik Ki Lau
- Shu Zhang (ORCID: https://orcid.org/0009-0005-6592-118X)
- Zhe Chen (ORCID: https://orcid.org/0009-0004-6605-8237)
- Keyi Dong
- Weronika M. Bartosik
- Bing Yang (ORCID: https://orcid.org/0009-0004-8590-5358)
- Abraham J. Horrillo (ORCID: https://orcid.org/0000-0001-6334-7229)
Institutions
- Gladstone Institutes (US)
- University of California, San Francisco (US)
- University of California San Diego (US)
- Chan Zuckerberg Initiative (United States) (US)
- Broad Center (US)
- Epigenomics (Germany) (DE)
- Tetra Tech (United States) (US)
Publication Details
- Journal
- Science
- Published
- 2026-07-23
- DOI
- https://doi.org/10.1126/science.adv5434
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Gladstone Institutes
- Saving Tiny Hearts Society
- Roddenberry Foundation
- Additional Ventures
- National Institutes of Health
- National Heart, Lung, and Blood Institute