N-methyladenosine RNA Modification Regulates Embryonic Neural Stem Cell Self-renewal Through Histone Modifications

Overview

Journal Nat Neurosci

Date 2018 Jan 17

PMID 29335608

Citations 239

Authors

Yang Wang

Yue Li

Minghui Yue

Jun Wang

Sandeep Kumar

Robert J Wechsler-Reya

Zhaolei Zhang

Yuya Ogawa

Manolis Kellis

Gregg Duester

Jing Crystal Zhao

Affiliations

Soon will be listed here.

Abstract

Internal N-methyladenosine (mA) 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 mA 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 mA 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 mA regulates histone modification in part by destabilizing transcripts that encode histone-modifying enzymes. Our results suggest an essential role for mA in development and reveal mA-regulated histone modifications as a previously unknown mechanism of gene regulation in mammalian cells.

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