Disruption of the Caenorhabditis elegans Integrator complex triggers a non-conventional transcriptional mechanism beyond snRNA genes

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.