KDM3A and KDM3B regulate alternative splicing in mouse pluripotent stem cells

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-05-08 DOI:10.1016/j.isci.2025.112612

Caleb M. Dillingham , Harshini Cormaty , Ellen C. Morgan , Andrew I. Tak , Dakarai E. Esgdaille , Paul L. Boutz , Rupa Sridharan

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引用次数: 0

Abstract

Histone modifying enzymes are crucial in preserving cell identity by establishing a conducive chromatin environment for lineage specific transcription factor activity. Mouse pluripotent embryonic stem cells (mESCs) show lower levels of gene repression associated with histone modifications, facilitating rapid response to differentiation cues. The KDM3 family of histone demethylases removes repressive histone H3 lysine 9 dimethylation (H3K9me2). We uncover a surprising role for the KDM3 proteins in the post-transcriptional regulation of mESCs. Proteomic analysis shows KDM3A and KDM3B interacting with RNA processing factors such as EFTUD2 and PRMT5. Acute degradation of the endogenous KDM3A and KDM3B proteins resulted in altered splicing independent of H3K9me2 status or catalytic activity. These splicing changes partially resemble the splicing pattern of the more blastocyst-like ground state of pluripotency and occur in important chromatin and transcription factors such as Dnmt3b and Tcf12. Our findings reveal non-canonical roles of histone demethylating enzymes in splicing to regulate cell identity.

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KDM3A和KDM3B调节小鼠多能干细胞的选择性剪接

组蛋白修饰酶是通过建立一个有利于谱系特异性转录因子活性的染色质环境来保护细胞身份的关键。小鼠多能胚胎干细胞（mESCs）显示出与组蛋白修饰相关的较低水平的基因抑制，促进对分化线索的快速反应。KDM3家族的组蛋白去甲基化酶去除抑制性组蛋白H3赖氨酸9二甲基化（H3K9me2）。我们发现了KDM3蛋白在mESCs转录后调控中的一个令人惊讶的作用。蛋白质组学分析显示KDM3A和KDM3B与EFTUD2和PRMT5等RNA加工因子相互作用。内源性KDM3A和KDM3B蛋白的急性降解导致剪接改变，而不依赖于H3K9me2状态或催化活性。这些剪接变化部分类似于更像囊胚的多能性基态的剪接模式，发生在重要的染色质和转录因子中，如Dnmt3b和Tcf12。我们的研究结果揭示了组蛋白去甲基化酶在剪接中调节细胞身份的非规范作用。

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

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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