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

METTL14 regulates chromatin bivalent domains in mouse embryonic stem cells

Mandi Mu  1 , Xinze Li  1 , Li Dong  1 , Jin Wang  1 , Qingqing Cai  1 , Yajun Hu  1 , Duanduan Wang  1 , Peng Zhao  1 , Lei Zhang  1 , Daixuan Zhang  1 , Siyi Cheng  1 , Li Tan  2 , Feizhen Wu  1 , Yujiang Geno Shi  1 , Wenqi Xu  3 , Yang Shi  4 , Hongjie Shen  5
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METTL14 regulates chromatin bivalent domains in mouse embryonic stem cells

Mandi Mu et al. Cell Rep. .
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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.

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Conflict of interest statement

Declaration of interests Y.S. is a co-founder and member of the Scientific Advisory Broad of K36 Therapeutics and ABio, Inc. Y.S. is also a member of the scientific advisory board of Epicrispr Biotechnologies, Inc., and a member of the MD Anderson External Advisory Board. Y.S. holds equity in Active Motif, K36 Therapeutics, ABio, Inc., and Epicrispr Biotechnologies, Inc.

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