Disruption of the Caenorhabditis elegans Integrator complex triggers a non-conventional transcriptional mechanism beyond snRNA genes
Disruption of the Caenorhabditis elegans Integrator complex triggers a non-conventional transcriptional mechanism beyond snRNA genes
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DOI：
10.1371/journal.pgen.1007981
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发表时间：
2019-02-01
期刊：
影响因子：
4.5
通讯作者：
Cabello, Juan
中科院分区：
文献类型：
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作者：
Gomez-Orte, Eva;Saenz-Narciso, Beatriz;Cabello, Juan
基因表达通常通过转录因子和RNA聚合酶II（RNAP II）募集到基因启动子区的特定序列来调节。整合子复合物介导小核RNA（snRNA）的加工以及响应于生长因子在特定基因处暂停的RNAP II的起始和释放。这里我们展示了在C中。在线虫中，整合子复合物的破坏导致位于snRNA基因座下游的基因通过基于缺乏snRNA加工的非常规转录机制转录。RNAP II通读产生含有snRNA、基因间区域和位于有义的下游基因的成熟mRNA的长嵌合RNA。在U1和U2来源的sn-mRNA的情况下，这些嵌合sn-mRNA保持为未翻译的长非编码RNA，但在SL来源的sn-mRNA的情况下可以翻译为蛋白质。由整合子复合物的破坏引起的转录效应不限于位于snRNA基因座下游的基因，而且还影响信号转导的关键调节因子，如激酶和磷酸酶。我们的研究结果强调，这些转录改变可能是背后的整合子复合物和肿瘤transformation.Author摘要基因转录谱的突变之间的相关性决定了一个有机体的发育状态。在胚胎发生、衰老、饥饿或任何生命周期阶段，生物体表达特定的基因组，这些基因组必须在其他阶段被关闭，以维持细胞的正确代谢和分化状态。破坏信号通路控制的突变可能导致某些类型的肿瘤。这种情况发生在编码整合子复合物的基因突变中，整合子复合物是一种参与小核RNA（snRNA）加工的多蛋白质复合物。在这里，我们揭示了一个主要的机制，潜在的基因表达变化的突变体影响的整合剂复合物。使用秀丽隐杆线虫模型，我们描述了如何缺乏snRNA加工导致转录的基因位于下游的snRNA位点。这种主要的改变不仅限于这些基因，而且对参与蛋白质磷酸化修饰调节信号通路的其他基因的表达具有广泛的影响。
Gene expression is generally regulated by recruitment of transcription factors and RNA polymerase II (RNAP II) to specific sequences in the gene promoter region. The Integrator complex mediates processing of small nuclear RNAs (snRNAs) as well as the initiation and release of paused RNAP II at specific genes in response to growth factors. Here we show that in C. elegans, disruption of the Integrator complex leads to transcription of genes located downstream of the snRNA loci via a non-conventional transcription mechanism based on the lack of processing of the snRNAs. RNAP II read-through generates long chimeric RNAs containing snRNA, the intergenic region and the mature mRNA of the downstream gene located in sense. These chimeric sn-mRNAs remain as untranslated long non-coding RNAs, in the case of U1- and U2-derived sn-mRNAs, but can be translated to proteins in the case of SL-derived sn-mRNAs. The transcriptional effect caused by disruption of the Integrator complex is not restricted to genes located downstream of the snRNA loci but also affects key regulators of signal transduction such as kinases and phosphatases. Our findings highlight that these transcriptional alterations may be behind the correlation between mutations in the Integrator complex and tumor transformation.Author summary The gene transcription profile determines the developmental state of an organism. During embryogenesis, aging, starvation or any lifecycle stage, organisms express specific sets of genes that must be turned off at other stages to maintain the correct metabolic and differentiated state of the cells. Mutations that disrupt control of signaling pathways may give rise to certain types of tumors. This happens with mutations in genes coding for the Integrator complex, a multi-protein complex involved in the processing of small nuclear RNAs (snRNAs). Here, we uncover a major mechanism underlying gene expression changes in mutants affecting the Integrator complex. Using a Caenorhabditis elegans model, we describe how the lack of snRNA processing leads to transcription of genes located downstream of the snRNA loci. This primary alteration is not restricted only to those genes but has a broad effect on the expression of other genes involved in the regulation of signaling pathways by protein phospho-modification.