METTL14 Is a Chromatin Regulator Independent of Its RNA N6-Methyladenosine Methyltransferase Activity

Authors

Xiaoyang Dou
Lulu Huang
Yu Xiao
Chang Liu
Yini Li
Xinning Zhang
Lishan Yu
Ran Zhao
Lei Yang
Chuan Chen
Xianbin Yu
Boyang Gao
Meijie Qi
Yawei Gao
Bin Shen
Shuying Sun
Chuan He
Jun Liu

Publication Date

9-14-2023

Journal

Protein & Cell

Abstract

METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell (mESC). While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-independent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification. Mechanistically, METTL14, but not METTL3, binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression. The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs. This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.

Keywords

Animals, Mice, Methylation, Chromatin, Histones, RNA, Messenger, Methyltransferases, RNA

Comments

PMID: 37030005