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The influence of Argonaute proteins on alternative RNA splicing

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Alternative splicing of precursor RNAs is an important process in multicellular species because it impacts several aspects of gene expression: from the increase of protein repertoire to the level of expression. A large body of evidences demonstrates that factors regulating chromatin and transcription impact the outcomes of alternative splicing. Argonaute (AGO) proteins were known to play key roles in the regulation of gene expression at the post‐transcriptional level. More recently, their role in the nucleus of human somatic cells has emerged. Here, we will discuss some of the nuclear functions of AGO, with special emphasis on alternative splicing. The AGO‐mediated modulation of alternative splicing is based on several properties of these proteins: their binding to transcripts on chromatin and their interactions with many proteins, especially histone tail‐modifying enzymes, HP1γ and splicing factors. AGO proteins may favor a decrease in the RNA‐polymerase II kinetics at actively transcribed genes leading to the modulation of alternative splicing decisions. They could also influence alternative splicing through their interaction with core components of the splicing machinery and several splicing factors. We will discuss the modes of AGO recruitment on chromatin at active genes. We suggest that long intragenic antisense transcripts (lincRNA) might be an important feature of genes containing splicing events regulated by AGO. WIREs RNA 2015, 6:141–156. doi: 10.1002/wrna.1264 This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action
Schematic representation of the chromatin features and RNA polymerase II (RNAPII) presence along the CD44 gene. The bottom graph illustrates the human CD44 gene with the main promoter (black arrow), the constitutive exons (black scares) noted C1 to C5 and C16 to C19, and the variant exons (gray scares) in the middle noted v2 to v10. The bowls symbolize the nucleosomes which are whether enriched (red), partially enriched (red/brown), or poor (brown) in H3K9me3. The RNAPII (green form) crosses the gene quickly (fast symbol) and slows down in the region containing the alternative exons (slow symbol, and RNAPII form colored in black‐green). Enrichment of histone tail modifications was illustrated by colored area: H3K4me3 (orange) and H3K4me2 (yellow) were mainly present in the promoter region. H3K36me3 (blue area and dotted line) is enriched in the gene body. H3K9me3 (red) and H3K9me2 (red line) increase in the region containing variant exons, and are highest at the end of this region. Patterns of histone tail modifications were relativized by histone H3, indicating enrichment in histone modifications and not in nucleosomes. Accumulation of the RNAPII (green area and line) is mainly detected in the CD44 gene body into the region containing the variant exons. The representation illustrates data from Refs 6 and 50.
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Model of Argonaute recruitment to the chromatin via protein interactions or G‐rich sequences. AGO2 localization to chromatin also involved its interaction with one or more recruiting chromatin factors and may not be required RNA components (a). Interaction of AGO2 to pre‐mRNA splicing targets may involve flanking exonic sequences that are G‐rich (b). The splicing factors may specifically address the region of AGO enrichment in the transcriptome (c). The snRNAs and Dicer activity are not required per se for the AGO recruitment, and no change in the histone tails or RNA degradation activity are expected.
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Model of Argonaute recruitment to the chromatin through its interaction with an antisense transcript mediated by endogenous sense snRNAs. The AGO proteins are prerecruited on the chromatin through interactions with chromatin factors (a). Chromatin‐associated AGOs are mainly bound to sense snRNAs that could allow detection of antisense transcript (b). These antisense RNA specifies the locus where AGOs induce the recruitment of HKMTs (SUV39H1 and EHMT2) mediating the increase of H3K9me3 and HP1γ. This promotes the slowing down of RNAPII and influences the alternative splicing decisions. In the following step (c), the AGO proteins were found to be more associated with nascent sense transcript. If AGO2 on the chromatin has slicer activity, it might favor the antisense degradation that could amplify the RISC recruitment.
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Model of Argonaute recruitment to the chromatin through its interaction to the sense transcript mediated by antisense strand of small interfering RNA (siRNA), and its effects on alternative splicing decision. The antisense strand of ectopic siRNA mediates complementary recognition of the sense transcript (a). The AGO1 or AGO2 proteins lead to the recruitment of HP1α through an increase in H3K27me3 and H3K9me2 marks as well as a decrease in histone acetylation (b). This promotes a slowing down of the elongative RNA polymerase II (RNAPII) and favors the inclusion of alternative exon in FN1 gene (c).
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Interactions of chromatin‐associated AGO1 and AGO2 with proteins identified by mass spectrometry (MS) after a double TAP‐tag purification. The factors are grouped by categories depending on their functions or families. The components of the chromatin are highlighted by the blue cloud. The splicing factors in the yellow squares are subdivided according to whether they belong to U2 or U5 spliceosome core complexes (factors indicated in gray have not been identified in MS analysis), or they belong to the regulatory factors. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are boxed in gray, other RNA‐binding proteins in light yellow, and other RNA‐induced silencing complex (RISC) factors in green. The protein interactions with AGO1 are symbolized by red arrows and those with AGO2 by blue arrows. The proteins bound by both AGO1 and AGO2 are indicated in black. The asterisks indicate already described interactions.
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Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action
RNA Processing > Splicing Regulation/Alternative Splicing

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