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.
bioRxiv. 2024 Jan 23:2023.05.31.543088. doi: 10.1101/2023.05.31.543088.
Histone modifying enzymes play a central role in maintaining cell identity by establishing a conducive chromatin environment for lineage specific transcription factor activity. Pluripotent embryonic stem cell (ESC) identity is characterized by a lower abundance of gene repression associated histone modifications that enables rapid response to differentiation cues. The KDM3 family of histone demethylases removes the repressive histone H3 lysine 9 dimethylation (H3K9me2). Here we uncover a surprising role for the KDM3 proteins in the maintenance of the pluripotent state through post-transcriptional regulation. We find that KDM3A and KDM3B interact with RNA processing factors such as EFTUD2 and PRMT5. Acute selective 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 occurred 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，在维持细胞特性方面发挥核心作用。多能胚胎干细胞（ESC）的特性是与基因抑制相关的组蛋白修饰丰度较低，这使得细胞能够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）。在这里，我们发现KDM3蛋白在通过转录后调控维持多能状态方面发挥了惊人的作用。我们发现KDM3A和KDM3B与诸如EFTUD2和PRMT5等RNA加工因子相互作用。内源性KDM3A和KDM3B蛋白的急性选择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础状态的剪接模式，并且发生在诸如 和 等重要的染色质和转录因子中。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特性的非经典作用。
