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

N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications.

Author information

1
Tumor Initiation and Maintenance Program, NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
2
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
3
Division of Reproductive Sciences, Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
4
Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
5
Development, Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
6
Department of Molecular Genetics, The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
7
Tumor Initiation and Maintenance Program, NCI-designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. czhao@sbpdiscovery.org.

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.

PMID:
29335608
PMCID:
PMC6317335
DOI:
10.1038/s41593-017-0057-1
[Indexed for MEDLINE]
Free PMC Article

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