METTL14 is a chromatin regulator independent of its RNA N6-methyladenosine methyltransferase activity

被引：42

作者：

Dou, Xiaoyang ^{[1
,2
,3
]}

Huang, Lulu ^{[4
]}

Xiao, Yu ^{[1
,2
,3
]}

Liu, Chang ^{[1
,2
,3
]}

Li, Yini ^{[5
,6
]}

Zhang, Xinning ^{[4
]}

Yu, Lishan ^{[4
]}

Zhao, Ran ^{[4
]}

Yang, Lei ^{[7
]}

Chen, Chuan ^{[8
]}

Yu, Xianbin ^{[1
,2
,3
]}

Gao, Boyang ^{[1
,2
,3
]}

Qi, Meijie ^{[9
]}

Gao, Yawei ^{[10
]}

Shen, Bin ^{[11
]}

Sun, Shuying ^{[5
,6
]}

He, Chuan ^{[1
,2
,3
,12
]}

Liu, Jun ^{[4
]}

机构：

[1] Univ Chicago, Dept Chem, Chicago, IL 60637 USA

[2] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA

[3] Howard Hughes Med Inst, Chicago, IL 60637 USA

[4] Peking Univ, Peking Tsinghua Ctr Life Sci, Sch Life Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China

[5] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Brain Sci Inst, Sch Med, Baltimore, MD 21205 USA

[7] Tongji Univ, Shanghai East Hosp, Inst Regenerat Med, Frontier Sci Ctr Stem Cell Res,Frontier Sci Ctr St, Shanghai 200120, Peoples R China

[8] Zhejiang Univ, Inst Translat Med, Sch Med, Hangzhou 310029, Peoples R China

[9] Univ Sci & Technol China, Affiliated Hosp USTC 1, Ctr Reprod Med, Div Life Sci & Med, Hefei 230000, Peoples R China

[10] Tongji Univ, Shanghai Matern & Infant Hosp 1, Clin & Translat Res Ctr, Frontier Sci Ctr Stem Cell Res,Shanghai Key Lab Si, Shanghai 200092, Peoples R China

[11] Nanjing Med Univ, Womens Hosp, Nanjing Matern & Child Hlth Care Hosp, Ctr Global Hlth,Gusu Sch,State Key Lab Reprod Med, Nanjing 211166, Peoples R China

[12] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA

来源：

PROTEIN & CELL | 2023年 / 14卷 / 09期

基金：

中国国家自然科学基金;

关键词：

METTL14; chromatin; m(6)A-independent; mESC differentiation; NUCLEAR-RNA; TRANSCRIPTION FACTORS; SELF-RENEWAL; METHYLATION; TRANSLATION; N6-METHYLADENOSINE;

D O I：

10.1093/procel/pwad009

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m(6)A methyltransferase complex (MTC) that installs m(6)A. 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 m(6)A 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 m(6)A-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 m(6)A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.

引用

页码：683 / 697

页数：15

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