Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease-linked transcription factor

• 成果类型: Article
• 署名作者: Grant, Zoe L.; Kuang, Shuzhen; Zhang, Shu; Horrillo, Abraham J.; Chen, Zhe; Rao, Kavitha S.; Celen, Cemre; Kameswaran, Vasumathi; Joubran, Carine; Lau, Pik Ki; Dong, Keyi; Yang, Bing; Bartosik, Weronika M.; Zemke, Nathan R.; Ren, Bing; Srivastava, Deepak; Kathiriya, Irfan S.; Pollard, Katherine S.; Bruneau, Benoit G.
• 署名单位: University of California System; University of California San Francisco; The J David Gladstone Institutes; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Chan Zuckerberg Initiative (CZI); University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adv5434
• 发表日期: 2026-07-23
• 页码: eadv5434
• 关键词: HOLT-ORAM-SYNDROME; GLOBIN LOCUS REQUIRES; gene-expression; TBX5; cohesin; genome; enhancer; reveals; ctcf; atrial

摘要

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.