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

作者：Shaohai Fang, Jia Li, Yang Xiao, Minjung Lee, Lei Ming 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, Yun Feng Huang · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-12325-z · 被引用次数：88 · 研究领域：Congenital heart defects research、Epigenetics and DNA Methylation、RNA modifications and cancer

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.