Muscle regeneration controlled by a designated DNA dioxygenase

Hongye Wang,Yile Huang,Ming Yu,Bing Li,Yang Yu,Sheng Li,Huating Wang,Ping Hu,Guoliang Xu,Hao Sun

doi:10.1038/s41419-021-03817-2

Abstract

Tet dioxygenases are responsible for the active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2, but not Tet1 and Tet3, is specifically required for muscle regeneration in vivo. Loss of Tet2 leads to severe muscle regeneration defects. Further analysis indicates that Tet2 regulates myoblast differentiation and fusion. Tet2 activates transcription of the key differentiation modulator Myogenin (MyoG) by actively demethylating its enhancer region. Re-expressing of MyoG in Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 enhances MyoD binding by demethylating the flanking CpG sites of E boxes to facilitate the recruitment of active histone modifications and increase chromatin accessibility and activate its transcription. These findings shed new lights on DNA methylation and pioneer transcription factor activity regulation.

Highlights

Skeletal muscles can regenerate due to the existence of muscle stem cells (MuSCs)[1,2]
Wang et al Cell Death and Disease (2021)12:535 mediated active DNA demethylation at the CpG sites near E boxes enhanced the MyoD binding and increased the chromatin accessibility and active histone modification recruitment. These results revealed the specific functions of Ten-Eleven Translocation (Tet)[2] in vivo during muscle regeneration and shed new lights on understanding the mechanism of transcription regulated by DNA methylation
The regeneration defects were observed as indicated by hematoxylin and eosin (H&E) staining and decreased number of Myh3+ newly formed myofibers in Tet[2] KO mice (Fig. 1B–D)

Summary

Introduction

Skeletal muscles can regenerate due to the existence of muscle stem cells (MuSCs)[1,2]. Skeletal muscle development and postnatal muscle regeneration are tightly regulated by muscle-specific transcriptional factors. MyoD is considered to be the master regulator of myogenesis[5], which recognizes and binds E box to activate transcription of target genes[6,7,8,9,10]. Another transcription factors Myogenin (MyoG) can regulate myogenesis[11,12]. MyoD directly activates the transcription of MyoG by binding the E-box at its core promoter[8]. Despite the accumulating amount of excellent works about the mechanism of MyoD dependent transcription activation are still needed

Methods

Results

Conclusion