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Epigenetics Chromatin. 2019 Jun 4;12(1):32. doi: 10.1186/s13072-019-0281-x.

Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation.

Zhang T1,2, Guan X1,2, Choi UL1,2, Dong Q3, Lam MMT1,2, Zeng J1,2, Xiong J3, Wang X1,2, Poon TCW1,2, Zhang H1,2, Zhang X1,2, Wang H4, Xie R1,2, Zhu B3,5, Li G6,7.

Author information

1
Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau.
2
Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau.
3
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
4
The State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
5
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
6
Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau. gangli@um.edu.mo.
7
Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau. gangli@um.edu.mo.

Abstract

BACKGROUND:

TET-mediated oxidation of 5-mC participates in both passive and active DNA demethylation, which exerts a significant influence on diverse biological processes. Mass spectrometry has identified multiple phosphorylation sites of TET2. However, the functions of these phosphosites and their corresponding kinases are mostly unknown.

RESULTS:

Here, we showed that AMP-activated protein kinase (AMPK) phosphorylates murine TET2 at the serine residue 97 (S97), and the phosphorylation enhances TET2 stability through promoting its binding to 14-3-3β. AMPK ablation resulted in decreased global 5-hmC levels at the myotube stages, severe differentiation defects of C2C12 cells and significantly, total loss of expression of Pax7. Genome-wide analyses revealed increased DNA methylation at genic and enhancer regions of AMPK-null myoblasts and myotubes. Using CRISPR/Cas9 technology, we showed that a novel enhancer, which is hypermethylated in AMPK-null cells, regulates Pax7 expression. The phospho-mimicking mutant, TET2-S97E, could partly rescue the differentiation defect in AMPK-ablated C2C12 cells.

CONCLUSIONS:

Together, our data demonstrated that AMPK is a critical regulator of myogenesis, partly through phosphorylating TET2.

KEYWORDS:

AMPK; Myogenesis; PAX7; Phosphorylation; TET2

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