Loss of ten-eleven translocation 2 induces cardiac hypertrophy and fibrosis through modulating ERK signaling pathway

Author:

Tao Huikang123,Xu Weize13,Qu Wenzheng123,Gao Hui13,Zhang Jinyu123ORCID,Cheng Xuejun13,Liu Ning2ORCID,Chen Jinghai2,Xu Guo-Liang45,Li Xuekun123ORCID,Shu Qiang13

Affiliation:

1. The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China

2. The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China

3. National Clinical Research Center for Child Health, Hangzhou 310052, China

4. Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China

5. Laboratory of Medical Epigenetics, Institute of Biomedical Sciences, Medical College of Fudan University, Chinese Academy of Medical Sciences (RU069), Shanghai 200032, China

Abstract

Abstract 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.

Funder

Science Technology Department of Zhejiang Province

Natural Science Foundation of Zhejiang Province

Fundamental Research Funds for the Central Universities

National Natural Science Foundation of China

Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents

Key Research and Development Program of Zhejiang Province

Publisher

Oxford University Press (OUP)

Subject

Genetics(clinical),Genetics,Molecular Biology,General Medicine

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