Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA.
Texas Heart Institute, Cardiomyocyte Renewal Lab, Houston, TX, 77030, USA.
Nat Commun. 2019 Sep 20;10(1):4297. doi: 10.1038/s41467-019-12325-z.
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.
Tet 介导的 DNA 去甲基化在塑造表观遗传景观和染色质可及性以控制基因表达方面发挥着重要作用。虽然有几项研究表明 Tet 在调节胚胎发育方面起着关键作用，但它们在心脏发育中的功能知之甚少。在这里，我们分析了人类和小鼠早期心脏发育过程中的 DNA 甲基化和羟甲基化动态。我们发现，小鼠中 Tet2 和 Tet3 的心脏特异性缺失（Tet2/3-DKO）导致心室非致密性心肌病（NCC）伴胚胎致死。单细胞 RNA-seq 分析显示，Tet2/3 耗竭后，心脏组织中的心肌细胞数量减少和转录重编程。Tet2/3-DKO 小鼠中 DNA 去甲基化受损和染色质可及性降低进一步损害了 Ying-yang1（YY1）与其基因组靶标的结合，并扰乱了心脏发育关键基因的高级染色质组织。我们的研究为 Tet 在调节早期心脏发育过程中的 DNA 甲基化动态和染色质组织方面的生理作用提供了证据。
