Changes in the cellular environment result in chromatin structure alteration, which in turn regulates gene expression. To learn about the effect of the cellular environment on the transcriptome, we studied the H3K9 demethylase KDM3A. Using RNA-seq, we found that KDM3A regulates the transcription and alternative splicing of genes associated with cell cycle and DNA damage. We showed that KDM3A undergoes phosphorylation by PKA at serine 265 following DNA damage, and that the phosphorylation is important for proper cell-cycle regulation. We demonstrated that SAT1 alternative splicing, regulated by KDM3A, plays a role in cell-cycle regulation. Furthermore we found that KDM3A's demethylase activity is not needed for SAT1 alternative splicing regulation. In addition, we identified KDM3A's protein partner ARID1A, the SWI/SNF subunit, and SRSF3 as regulators of SAT1 alternative splicing and showed that KDM3A is essential for SRSF3 binding to SAT1 pre-mRNA. These results suggest that KDM3A serves as a sensor of the environment and an adaptor for splicing factor binding. Our work reveals chromatin sensing of the environment in the regulation of alternative splicing.

中文翻译：

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KDM3A 调节 DNA 损伤后细胞周期基因的选择性剪接


细胞环境的变化导致染色质结构改变，进而调节基因表达。为了了解细胞环境对转录组的影响，我们研究了 H3K9 去甲基酶 KDM3A。使用 RNA-seq，我们发现 KDM3A 调节与细胞周期和 DNA 损伤相关的基因的转录和选择性剪接。我们发现，DNA 损伤后，KDM3A 在丝氨酸 265 处被 PKA 磷酸化，并且磷酸化对于正确的细胞周期调节非常重要。我们证明了由 KDM3A 调节的 SAT1 选择性剪接在细胞周期调节中发挥作用。此外，我们发现 SAT1 选择性剪接调节不需要 KDM3A 的去甲基酶活性。此外，我们还确定了 KDM3A 的蛋白伴侣 ARID1A、SWI/SNF 亚基和 SRSF3 作为 SAT1 选择性剪接的调节因子，并表明 KDM3A 对于 SRSF3 与 SAT1 前体 mRNA 的结合至关重要。这些结果表明 KDM3A 充当环境传感器和剪接因子结合的适配器。我们的工作揭示了染色质对环境的感知在选择性剪接的调节中的作用。