Variation of C-terminal domain governs RNA polymerase II genomic locations and alternative splicing in eukaryotic transcription.
Variation of C-terminal domain governs RNA polymerase II genomic locations and alternative splicing in eukaryotic transcription.
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C 端结构域的变异控制着 RNA 聚合酶 II 基因组位置和真核转录中的选择性剪接。
DOI：
10.1101/2024.01.01.573828
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Zhang,YJessie
中科院分区：
文献类型：
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作者：
Zhang,Qian;Kim,Wantae;Panina,Svetlana;Mayfield,JoshuaE;Portz,Bede;Zhang,YJessie
RPB 1的C-末端结构域（CTD）通过在磷酸化后将调节因子募集到RNA Pol II来协调转录。随着CTD驱动基因位点上的冷凝物形成，CTD介导的转录调节因子募集如何影响冷凝物形成的分子机制仍不清楚。我们的研究揭示了磷酸化可逆地溶解由非磷酸化CTD诱导的相分离。磷酸化CTD与转录调节因子特异性结合后，形成与未磷酸化CTD不同的缩合物。功能研究表明，具有不同缩合特性的CTD变体在细胞中的启动子结合和mRNA共加工方面表现出差异。值得注意的是，不同的CTD长度影响RNA加工机制和选择性剪接结果的组装，这反过来又影响细胞生长，将CTD变异/长度的进化与从酵母到人类的剪接复杂性联系起来。这些发现为一个模型提供了令人信服的证据，其中翻译后修饰使功能专门化的缩合物的过渡成为可能，突出了CTD缩合和剪接之间的共同进化联系。
The C-terminal domain of RPB1 (CTD) orchestrates transcription by recruiting regulators to RNA Pol II upon phosphorylation. With CTD driving condensate formation on gene loci, the molecular mechanism behind how CTD-mediated recruitment of transcriptional regulators influences condensates formation remains unclear. Our study unveils that phosphorylation reversibly dissolves phase separation induced by the unphosphorylated CTD. Phosphorylated CTD, upon specific association with transcription regulators, forms distinct condensates from unphosphorylated CTD. Functional studies demonstrate CTD variants with diverse condensation properties exhibit differences in promoter binding and mRNA co-processing in cells. Notably, varying CTD lengths influence the assembly of RNA processing machinery and alternative splicing outcomes, which in turn affects cellular growth, linking the evolution of CTD variation/length with the complexity of splicing from yeast to human. These findings provide compelling evidence for a model wherein post-translational modification enables the transition of functionally specialized condensates, highlighting a co-evolution link between CTD condensation and splicing.