Dillingham Caleb M, Cormaty Harshini, Morgan Ellen C, Tak Andrew I, Esgdaille Dakarai E, Boutz Paul L, Sridharan Rupa
Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53792, USA.
iScience. 2025 May 8;28(6):112612. doi: 10.1016/j.isci.2025.112612. eCollection 2025 Jun 20.
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 and . Our findings reveal non-canonical roles of histone demethylating enzymes in splicing to regulate cell identity.
组蛋白修饰酶通过为谱系特异性转录因子活性建立有利的染色质环境，在维持细胞身份方面至关重要。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，有助于对分化信号做出快速反应。组蛋白去甲基化酶KDM3家族可去除抑制性组蛋白H3赖氨酸9二甲基化（H3K9me2）。我们发现KDM3蛋白在mESCs的转录后调控中发挥了惊人的作用。蛋白质组学分析表明，KDM3A和KDM3B与RNA加工因子如EFTUD2和PRMT5相互作用。内源性KDM3A和KDM3B蛋白的急性降解导致剪接改变，这与H3K9me2状态或催化活性无关。这些剪接变化部分类似于多能性更强的囊胚样基态的剪接模式，并且发生在重要的染色质和转录因子中，如 和 。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经典作用。
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