Tet inactivation disrupts YY1 binding and long-range chromatin interactions during embryonic heart development

Shaohai Fang, Jia Li, Yang Xiao, Minjung Lee, Lei Guo, Wei Han, Tingting Li, Matthew C. Hill, Tingting Hong, William Mo, Rang Xu, Ping Zhang, Fen Wang, Jiang Chang, Yubin Zhou, Deqiang Sun (), James F. Martin () and Yun Huang ()
Additional contact information
Shaohai Fang: Texas A&M University
Jia Li: Texas A&M University
Yang Xiao: Texas Heart Institute, Cardiomyocyte Renewal Lab
Minjung Lee: Texas A&M University
Lei Guo: Texas A&M University
Wei Han: Texas A&M University
Tingting Li: Texas A&M University
Matthew C. Hill: Baylor College of Medicine, One Baylor Plaza
Tingting Hong: Texas A&M University
William Mo: Texas A&M University
Rang Xu: Shanghai Jiao Tong University
Ping Zhang: Shanghai Jiao Tong University
Fen Wang: Texas A&M University
Jiang Chang: Texas A&M University
Yubin Zhou: Texas A&M University
Deqiang Sun: Texas A&M University
James F. Martin: Texas Heart Institute, Cardiomyocyte Renewal Lab
Yun Huang: Texas A&M University

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract Tet-mediated DNA demethylation plays an important role in shaping the epigenetic landscape and chromatin accessibility to control gene expression. While several studies demonstrated pivotal roles of Tet in regulating embryonic development, little is known about their functions in heart development. Here we analyze DNA methylation and hydroxymethylation dynamics during early cardiac development in both human and mice. We find that cardiac-specific deletion of Tet2 and Tet3 in mice (Tet2/3-DKO) leads to ventricular non-compaction cardiomyopathy (NCC) with embryonic lethality. Single-cell RNA-seq analyses reveal a reduction in cardiomyocyte numbers and transcriptional reprogramming in cardiac tissues upon Tet2/3 depletion. Impaired DNA demethylation and reduced chromatin accessibility in Tet2/3-DKO mice further compromised Ying-yang1 (YY1) binding to its genomic targets, and perturbed high-order chromatin organization at key genes involved in heart development. Our studies provide evidence of the physiological role of Tet in regulating DNA methylation dynamics and chromatin organization during early heart development.

Date: 2019
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DOI: 10.1038/s41467-019-12325-z

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