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

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

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

Author: Xiaoyang DOU ¹ ; Lulu HUANG ² ; Yu XIAO ¹ ; Chang LIU ¹ ; Yini LI ³ ; Xinning ZHANG ² ; Lishan YU ² ; Ran ZHAO ² ; Lei YANG ⁴ ; Chuan CHEN ⁵ ; Xianbin YU ¹ ; Boyang GAO ¹ ; Meijie QI ⁶ ; Yawei GAO ⁷ ; Bin SHEN ⁸ ; Shuying SUN ³ ; Chuan HE ¹ ; Jun LIU ²
Author Information

1. Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
2. State Key Laboratory of Protein and Plant Gene Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing 100871, China.
3. Department of Physiology and Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4. Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China.
5. The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China.
6. Division of Life Sciences and Medicine, Center for Reproductive Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230000, China.
7. Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
8. State Key Laboratory of Reproductive Medicine, Center for Global Health, Gusu School, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, 211166, China.
Publication Type:Research Support, N.I.H., Extramural
Keywords: H3K27me3; METTL14; chromatin; m6A-independent; mESC differentiation
MeSH: Animals; Mice; Methylation; Chromatin; Histones/metabolism*; RNA, Messenger/genetics*; Methyltransferases/metabolism*; RNA/metabolism*
From: Protein & Cell 2023;14(9):683-697
CountryChina
Language:English
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.