The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.
The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China.
Hum Mol Genet. 2021 May 29;30(10):865-879. doi: 10.1093/hmg/ddab046.
The ten-eleven translocation (Tet) family of dioxygenases convert 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Previous studies have shown that 5hmC-mediated epigenetic modifications play essential roles in diverse biological processes and diseases. Here, we show that Tet proteins and 5hmC display dynamic features during postnatal cardiac development and that Tet2 is the predominant dioxygenase present in heart. Tet2 knockout results in abnormal cardiac function, progressive cardiac hypertrophy and fibrosis. Mechanistically, Tet2 deficiency leads to reduced hydroxymethylation in the cardiac genome and alters the cardiac transcriptome. Mechanistically, Tet2 loss leads to a decrease of Hspa1b expression, a regulator of the extracellular signal-regulated protein kinase (Erk) signaling pathway, which leads to over-activation of Erk signaling. Acute Hspa1b knock down (KD) increased the phosphorylation of Erk and induced hypertrophy of cardiomyocytes, which could be blocked by Erk signaling inhibitor. Consistently, ectopic expression of Hspa1b was able to rescue the deficits of cardiomyocytes induced by Tet2 depletion. Taken together, our study's results reveal the important roles of Tet2-mediated DNA hydroxymethylation in cardiac development and function.
十-十一易位（Tet）家族的双加氧酶将 5-甲基胞嘧啶转化为 5-羟甲基胞嘧啶（5hmC）。先前的研究表明，5hmC 介导的表观遗传修饰在多种生物过程和疾病中发挥着重要作用。在这里，我们表明 Tet 蛋白和 5hmC 在心脏出生后的发育过程中表现出动态特征，并且 Tet2 是心脏中主要存在的双加氧酶。Tet2 敲除会导致心脏功能异常、进行性心肌肥大和纤维化。在机制上，Tet2 缺乏会导致心脏基因组中羟甲基化减少，并改变心脏转录组。在机制上，Tet2 缺失会导致细胞外信号调节蛋白激酶（Erk）信号通路的调节因子 Hspa1b 表达减少，从而导致 Erk 信号过度激活。急性 Hspa1b 敲低（KD）增加了 Erk 的磷酸化，并诱导心肌细胞肥大，而 Erk 信号抑制剂可以阻断这一过程。一致地，Hspa1b 的异位表达能够挽救 Tet2 耗竭引起的心肌细胞缺陷。总之，我们的研究结果揭示了 Tet2 介导的 DNA 羟甲基化在心脏发育和功能中的重要作用。
