N 6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications

Nat Neurosci. 2018 Feb;21(2):195-206. doi: 10.1038/s41593-017-0057-1. Epub 2018 Jan 15.

Abstract

Internal N6-methyladenosine (m6A) modification is widespread in messenger RNAs (mRNAs) and is catalyzed by heterodimers of methyltransferase-like protein 3 (Mettl3) and Mettl14. To understand the role of m6A in development, we deleted Mettl14 in embryonic neural stem cells (NSCs) in a mouse model. Phenotypically, NSCs lacking Mettl14 displayed markedly decreased proliferation and premature differentiation, suggesting that m6A modification enhances NSC self-renewal. Decreases in the NSC pool led to a decreased number of late-born neurons during cortical neurogenesis. Mechanistically, we discovered a genome-wide increase in specific histone modifications in Mettl14 knockout versus control NSCs. These changes correlated with altered gene expression and observed cellular phenotypes, suggesting functional significance of altered histone modifications in knockout cells. Finally, we found that m6A regulates histone modification in part by destabilizing transcripts that encode histone-modifying enzymes. Our results suggest an essential role for m6A in development and reveal m6A-regulated histone modifications as a previously unknown mechanism of gene regulation in mammalian cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Self Renewal / genetics*
  • Cell Self Renewal / physiology
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology
  • Dactinomycin / pharmacology
  • Deoxyadenosines / genetics*
  • Deoxyadenosines / metabolism
  • Embryo, Mammalian
  • Female
  • Fibronectins / metabolism
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Histones / metabolism*
  • Male
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neural Stem Cells / physiology*
  • Neurogenesis / drug effects
  • Neurogenesis / genetics
  • Neurogenesis / physiology
  • PAX6 Transcription Factor / genetics
  • PAX6 Transcription Factor / metabolism
  • Protein Synthesis Inhibitors / pharmacology
  • RNA, Messenger / metabolism*

Substances

  • Deoxyadenosines
  • Fibronectins
  • Histones
  • N(6)-methyldeoxyadenosine
  • PAX6 Transcription Factor
  • Pax6 protein, mouse
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • extra domain A fibronectin, mouse
  • Dactinomycin
  • Methyltransferases
  • Mettl14 protein, mouse