METTL14 regulates chromatin bivalent domains in mouse embryonic stem cells

Mandi Mu; Xinze Li; Li Dong; Jin Wang; Qingqing Cai; Yajun Hu; Duanduan Wang; Peng Zhao; Lei Zhang; Daixuan Zhang; Siyi Cheng; Li Tan; Feizhen Wu; Yujiang Geno Shi; Wenqi Xu; Yang Shi; Hongjie Shen

doi:10.1016/j.celrep.2023.112650

METTL14 regulates chromatin bivalent domains in mouse embryonic stem cells

Cell Rep. 2023 Jun 27;42(6):112650. doi: 10.1016/j.celrep.2023.112650. Epub 2023 Jun 13.

Authors

Mandi Mu¹, Xinze Li¹, Li Dong¹, Jin Wang¹, Qingqing Cai¹, Yajun Hu¹, Duanduan Wang¹, Peng Zhao¹, Lei Zhang¹, Daixuan Zhang¹, Siyi Cheng¹, Li Tan², Feizhen Wu¹, Yujiang Geno Shi¹, Wenqi Xu³, Yang Shi⁴, Hongjie Shen⁵

Affiliations

¹ Longevity and Aging Institute, the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
² Longevity and Aging Institute, the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Fudan University, Shanghai, China.
³ Longevity and Aging Institute, the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Fudan University, Shanghai, China. Electronic address: wenqixu@fudan.edu.cn.
⁴ Ludwig Institute for Cancer Research, Oxford Branch, Oxford University, Oxford, UK. Electronic address: yang.shi@ludwig.ox.ac.uk.
⁵ Longevity and Aging Institute, the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Fudan University, Shanghai, China. Electronic address: hongjieshen@fudan.edu.cn.

PMID: 37314930
DOI: 10.1016/j.celrep.2023.112650

Abstract

METTL14 (methyltransferase-like 14) is an RNA-binding protein that partners with METTL3 to mediate N⁶-methyladenosine (m⁶A) methylation. Recent studies identified a function for METTL3 in heterochromatin in mouse embryonic stem cells (mESCs), but the molecular function of METTL14 on chromatin in mESCs remains unclear. Here, we show that METTL14 specifically binds and regulates bivalent domains, which are marked by trimethylation of histone H3 lysine 27 (H3K27me3) and lysine 4 (H3K4me3). Knockout of Mettl14 results in decreased H3K27me3 but increased H3K4me3 levels, leading to increased transcription. We find that bivalent domain regulation by METTL14 is independent of METTL3 or m⁶A modification. METTL14 enhances H3K27me3 and reduces H3K4me3 by interacting with and probably recruiting the H3K27 methyltransferase polycomb repressive complex 2 (PRC2) and H3K4 demethylase KDM5B to chromatin. Our findings identify an METTL3-independent role of METTL14 in maintaining the integrity of bivalent domains in mESCs, thus indicating a mechanism of bivalent domain regulation in mammals.

Keywords: CP: Molecular biology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chromatin* / metabolism
Histones* / metabolism
Lysine / metabolism
Mammals / metabolism
Methyltransferases* / metabolism
Mice
Mice, Knockout
Mouse Embryonic Stem Cells / metabolism
Polycomb Repressive Complex 2 / metabolism

Substances

Chromatin
Histones
Lysine
Polycomb Repressive Complex 2
Mettl14 protein, mouse
Methyltransferases