Rtf1-dependent transcriptional pausing regulates cardiogenesis.
Rtf1-dependent transcriptional pausing regulates cardiogenesis.
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Rtf1 依赖性转录暂停调节心脏发生。
DOI：
10.1101/2023.10.13.562296
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Chen,Jau-Nian
中科院分区：
文献类型：
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作者：
Langenbacher,AdamD;Lu,Fei;Tsang,Luna;Huang,ZiYiStephanie;Keer,Benjamin;Tian,Zhiyu;Eide,Alette;Pellegrini,Matteo;Nakano,Haruko;Nakano,Atsushi;Chen,Jau-Nian
在心脏发育过程中，一个良好表征的转录因子网络启动心脏基因表达，并定义了心脏祖细胞特化的精确时间和位置。然而，我们对调节心脏基因表达的启动后转录事件的理解仍然是不完整的。PAF 1C组分Rtf 1是一种转录调节蛋白，可调节RNA Pol II的暂停和延长以及共转录组蛋白修饰。在这里，我们报告说，Rtf 1是必不可少的鱼类和哺乳动物的心脏发生，在没有Rtf 1活性，心脏祖细胞逮捕在一个不成熟的状态。我们发现，Rtf 1的Plus 3结构域，这赋予与转录暂停和延长调节Spt 5的相互作用，是必要的心脏祖细胞的形成。ChIP-seq分析进一步揭示了rtf 1 morphants中心脏基因转录起始位点（TSS）周围RNA Pol II占据率的变化，反映了转录暂停的减少。有趣的是，rtf 1突变体和突变体中暂停释放的抑制恢复了心脏细胞的形成，并提高了关键心脏基因TSS的Pol II占用率。我们的研究结果强调了转录暂停在心脏发育背景下促进正常基因表达水平方面的关键作用。
During heart development, a well-characterized network of transcription factors initiates cardiac gene expression and defines the precise timing and location of cardiac progenitor specification. However, our understanding of the post-initiation transcriptional events that regulate cardiac gene expression is still incomplete. The PAF1C component Rtf1 is a transcription regulatory protein that modulates pausing and elongation of RNA Pol II, as well as cotranscriptional histone modifications. Here we report that Rtf1 is essential for cardiogenesis in fish and mammals, and that in the absence of Rtf1 activity, cardiac progenitors arrest in an immature state. We found that Rtf1’s Plus3 domain, which confers interaction with the transcriptional pausing and elongation regulator Spt5, was necessary for cardiac progenitor formation. ChIP-seq analysis further revealed changes in the occupancy of RNA Pol II around the transcription start site (TSS) of cardiac genes in rtf1 morphants reflecting a reduction in transcriptional pausing. Intriguingly, inhibition of pause release in rtf1 morphants and mutants restored the formation of cardiac cells and improved Pol II occupancy at the TSS of key cardiac genes. Our findings highlight the crucial role that transcriptional pausing plays in promoting normal gene expression levels in a cardiac developmental context.