HDAC2-mediated recruitment of METTL3 to chromatin regulates human embryonic stem cell differentiation.

IF 6.9 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-10-08 DOI:10.1016/j.celrep.2025.116414

Jie Yang, Yikang Yang, Xiafei Zhang, Chenchao Yan, Liwen Jiang, Donghui Zhang, Wei Jiang

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引用次数: 0

Abstract

N6-methyladenosine (m6A) modification and its methyltransferase METTL3 are crucial for pluripotency maintenance and early development, but the underlying mechanism is largely unclear. Here, we demonstrate that METTL3 directly interacts with the histone deacetylase HDAC2 in chromatin. HDAC2 knockout reduces METTL3 chromatin binding and m6A levels on HDAC2 target genes linked to lineage differentiation, whereas METTL3 deletion does not affect HDAC2 expression or histone acetylation. Knocking out either HDAC2 or METTL3 significantly impairs human embryonic stem cell differentiation. We further observe that genes with reduced m6A upon depletion of HDAC2 exhibit decreased RNA stability and translation, mediated by the m6A readers IGF2BPs and YTHDC2, respectively. Mechanistically, HDAC2 recruits METTL3 to mediate m6A deposition on target genes and regulate RNA stability and translation, thereby modulating stem cell lineage differentiation. These findings identify a functional interactor of METTL3 and clarify the role of the HDAC2-METTL3 axis in human ESCs.

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hdac2介导的METTL3向染色质募集调节人胚胎干细胞分化。

n6 -甲基腺苷（m6A）修饰及其甲基转移酶METTL3对多能性维持和早期发育至关重要，但其潜在机制在很大程度上尚不清楚。在这里，我们证明了METTL3直接与染色质中的组蛋白去乙酰化酶HDAC2相互作用。敲除HDAC2可降低与谱系分化相关的HDAC2靶基因上的METTL3染色质结合和m6A水平，而METTL3缺失不影响HDAC2表达或组蛋白乙酰化。敲除HDAC2或METTL3都会显著损害人类胚胎干细胞的分化。我们进一步观察到，在HDAC2缺失的情况下，m6A减少的基因表现出RNA稳定性和翻译下降，分别由m6A读取器igf2bp和YTHDC2介导。机制上，HDAC2招募METTL3介导m6A在靶基因上的沉积，调控RNA的稳定性和翻译，从而调控干细胞谱系分化。这些发现确定了METTL3的一个功能性相互作用因子，并阐明了HDAC2-METTL3轴在人类ESCs中的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.