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METTL14 Regulates Chromatin Bivalent Domains in Mouse Embryonic Stem Cells [RNA-seq]

ABSTRACT: METTL14 (methyltransferase-like 14) is an RNA binding protein that partners with METTL3 to mediate N6-methyladenosine (m6A) methylation of mRNA. Recent studies identified a function for METTL3 in heterochromatin and transcription, but the role of METTL14 in these contexts remains unclear. Here we show that METTL14 binds and regulates mouse embryonic stem cell bivalent domains, which are marked with tri-methylation at lysine 27 of histone H3 (H3K27me3) and tri-methylation at lysine 4 of histone H3 (H3K4me3). Knockout of Mettl14 results in decreased H3K27me3 but increased H3K4me3 levels at bivalent regions, resulting in the resolution of the bivalency and in increased transcription. We demonstrate that bivalent domain regulation by METTL14 is independent of METTL3 or m6A modification. Instead, METTL14 enhances H3K27me3 and reduces H3K4me3 by interacting with and probably recruiting the histone 3 lysine 27 (H3K27) methyltransferase complex PRC2 and the histone 3 lysine 4 (H3K4) demethylases KDM5B to chromatin. Our findings identify a METTL3-independent function of METTL14, important for maintaining the bivalent domains in mESCs, thus revealing a new mechanism of bivalent domain regulation in mammals.

ORGANISM(S): Mus musculus

PROVIDER: GSE206734 | GEO | 2023/06/19

REPOSITORIES: GEO

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Project description:The ability of cells to perceive and translate versatile cues into differential chromatin and transcriptional states is critical for many biological processes1-4. In plants, timely transition to a flowering state is crucial for successful reproduction5-7. EARLY BOLTING IN SHORT DAY (EBS) is a negative transcriptional regulator that prevents premature flowering in Arabidopsis8,9. Here, we revealed that bivalent bromo-adjacent homology (BAH)-plant homeodomain (PHD) reader modules of EBS bind H3K27me3 and H3K4me3, respectively. A subset of EBS-associated genes was co-enriched with H3K4me3, H3K27me3, and the Polycomb repressor complex 2 (PRC2). Interestingly, EBS adopts an auto-inhibition mode to mediate its binding preference switch between H3K27me3 and H3K4me3. This binding balance is critical because disruption of either EBS-H3K27me3 or EBS-H3K4me3 interaction induces EBS-mediated early floral transition. This study identifies a single bivalent chromatin reader capable of recognizing two antagonistic histone marks and reveals a distinct mechanism of interplay between active and repressive chromatin states.The ability of cells to perceive and translate versatile cues into differential chromatin and transcriptional states is critical for many biological processes1-4. In plants, timely transition to a flowering state is crucial for successful reproduction5-7. EARLY BOLTING IN SHORT DAY (EBS) is a negative transcriptional regulator that prevents premature flowering in Arabidopsis8,9. Here, we revealed that bivalent bromo-adjacent homology (BAH)-plant homeodomain (PHD) reader modules of EBS bind H3K27me3 and H3K4me3, respectively. A subset of EBS-associated genes was co-enriched with H3K4me3, H3K27me3, and the Polycomb repressor complex 2 (PRC2). Interestingly, EBS adopts an auto-inhibition mode to mediate its binding preference switch between H3K27me3 and H3K4me3. This binding balance is critical because disruption of either EBS-H3K27me3 or EBS-H3K4me3 interaction induces EBS-mediated early floral transition. This study identifies a single bivalent chromatin reader capable of recognizing two antagonistic histone marks and reveals a distinct mechanism of interplay between active and repressive chromatin states.v

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METTL14 Regulates Chromatin Bivalent Domains in Mouse Embryonic Stem Cells [RNA-seq]

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