m6A Regulates Neurogenesis and Neuronal Development by Modulating Histone Methyltransferase Ezh2

Junchen Chen; Yi-Chang Zhang; Chunmin Huang; Hui Shen; Baofa Sun; Xuejun Cheng; Yu-Jie Zhang; Yun-Gui Yang; Qiang Shu; Ying Yang; Xuekun Li

doi:10.1016/j.gpb.2018.12.007

m⁶A Regulates Neurogenesis and Neuronal Development by Modulating Histone Methyltransferase Ezh2

Genomics Proteomics Bioinformatics. 2019 Apr;17(2):154-168. doi: 10.1016/j.gpb.2018.12.007. Epub 2019 May 30.

Authors

Junchen Chen¹, Yi-Chang Zhang², Chunmin Huang³, Hui Shen¹, Baofa Sun⁴, Xuejun Cheng¹, Yu-Jie Zhang⁵, Yun-Gui Yang⁴, Qiang Shu⁶, Ying Yang⁷, Xuekun Li⁸

Affiliations

¹ 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.
² CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China.
³ CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
⁴ CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China; Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
⁵ The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China.
⁶ The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China. Electronic address: shuqiang@zju.edu.cn.
⁷ CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China; Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: yingyang@big.ac.cn.
⁸ 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. Electronic address: xuekun_li@zju.edu.cn.

Abstract

N⁶-methyladenosine (m⁶A), catalyzed by the methyltransferase complex consisting of Mettl3 and Mettl14, is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However, the roles and precise mechanisms of m⁶A modification in regulating neuronal development and adult neurogenesis remain unclear. Here, we examined the function of Mettl3, the key component of the complex, in neuronal development and adult neurogenesis of mice. We found that the depletion of Mettl3 significantly reduced m⁶A levels in adult neural stem cells (aNSCs) and inhibited the proliferation of aNSCs. Mettl3 depletion not only inhibited neuronal development and skewed the differentiation of aNSCs more toward glial lineage, but also affected the morphological maturation of newborn neurons in the adult brain. m⁶A immunoprecipitation combined with deep sequencing (MeRIP-seq) revealed that m⁶A was predominantly enriched in transcripts related to neurogenesis and neuronal development. Mechanistically, m⁶A was present on the transcripts of histone methyltransferase Ezh2, and its reduction upon Mettl3 knockdown decreased both Ezh2 protein expression and consequent H3K27me3 levels. The defects of neurogenesis and neuronal development induced by Mettl3 depletion could be rescued by Ezh2 overexpression. Collectively, our results uncover a crosstalk between RNA and histone modifications and indicate that Mettl3-mediated m⁶A modification plays an important role in regulating neurogenesis and neuronal development through modulating Ezh2.

Keywords: Ezh2; Mettl3; N(6)-methyladenosine (m(6)A); Neurogenesis; Neuronal development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / metabolism
Adult Stem Cells / cytology
Adult Stem Cells / metabolism
Animals
Brain / metabolism
Cell Differentiation / genetics
Cell Proliferation
Enhancer of Zeste Homolog 2 Protein / metabolism*
Gene Expression Regulation
Methyltransferases / metabolism
Mice, Inbred C57BL
Neural Stem Cells / cytology
Neural Stem Cells / metabolism
Neurogenesis* / genetics
Neurons / cytology
Neurons / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

RNA, Messenger
N-methyladenosine
Methyltransferases
Mettl3 protein, mouse
Enhancer of Zeste Homolog 2 Protein
Adenosine