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

Genomics, Proteomics & Bioinformatics (Apr 2019)

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

Affiliations

Junchen Chen: 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
Yi-Chang Zhang: 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
Chunmin Huang: 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
Hui Shen: 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
Baofa Sun: 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
Xuejun Cheng: 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
Yu-Jie Zhang: The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
Yun-Gui Yang: 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
Qiang Shu: The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; Corresponding authors.
Ying Yang: 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; Corresponding authors.
Xuekun Li: 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; Corresponding authors.

Journal volume & issue: Vol. 17, no. 2
pp. 154 – 168

Abstract

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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: N6-methyladenosine (m6A), Mettl3, Neurogenesis, Neuronal development, Ezh2

Published in Genomics, Proteomics & Bioinformatics

ISSN: 1672-0229 (Print); 2210-3244 (Online)
Publisher: Oxford University Press
Country of publisher: United Kingdom
LCC subjects: Science: Biology (General); Medicine: Medicine (General): Computer applications to medicine. Medical informatics
Website: https://academic.oup.com/gpb

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