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METTL14 是一种独立于其 RNA N6-甲基腺苷甲基转移酶活性的染色质调节因子。

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

机构信息

Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.

Howard Hughes Medical Institute, Chicago, IL 60637, USA.

出版信息

Protein Cell. 2023 Sep 14;14(9):683-697. doi: 10.1093/procel/pwad009.

DOI:10.1093/procel/pwad009
PMID:37030005
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10501186/
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.

摘要

METTL3 和 METTL14 是形成主要 RNA m6A 甲基转移酶复合物 (MTC) 核心异二聚体的两个组成部分，该复合物负责安装 m6A。令人惊讶的是，METTL3 或 METTL14 的耗竭对小鼠胚胎干细胞 (mESC) 的干性维持表现出不同的影响。尽管在 Mettl3 或 Mettl14 敲除 mESC 中分别观察到 RNA m6A 的可比全局低甲基化。Mettl14 敲除导致新生 RNA 合成全局减少，而 Mettl3 耗竭导致转录上调，表明 METTL14 可能在基因调控中具有 m6A 非依赖性作用。我们发现 METTL14 与抑制性 H3K27me3 修饰共定位。在机制上，METTL14 而不是 METTL3 结合 H3K27me3 并募集 KDM6B 诱导 H3K27me3 去甲基化，不依赖于 METTL3。METTL14 的耗竭导致 H3K27me3 水平全局增加以及全局基因抑制。METTL14 对 H3K27me3 调控的影响对于 mESC 从自我更新到分化的转变至关重要。这项工作揭示了 METTL14 通过不同于 METTL3 且独立于 m6A 的方式对异染色质的调控机制，并对 mESC 的转录调控、干性维持和分化产生关键影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/3966f1e05990/pwad009_fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/eb9de7e478ea/pwad009_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/ba25331b06e0/pwad009_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/854bc492f56b/pwad009_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/a51adeaa1620/pwad009_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/30084a79c3f8/pwad009_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/a393e37d6c26/pwad009_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/3966f1e05990/pwad009_fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/eb9de7e478ea/pwad009_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/ba25331b06e0/pwad009_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/854bc492f56b/pwad009_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/a51adeaa1620/pwad009_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/30084a79c3f8/pwad009_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/a393e37d6c26/pwad009_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf02/10501186/3966f1e05990/pwad009_fig7.jpg

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