Integrative transcriptomic analysis suggests new autoregulatory splicing events coupled with nonsense-mediated mRNA decay

Dmitri Pervouchine, Yaroslav Popov, Andy Berry, Beatrice Borsari, Adam Frankish, Roderic Guigó

    Research output: Contribution to journalArticlepeer-review

    19 Citations (Scopus)

    Abstract

    Nonsense-mediated decay (NMD) is a eukaryotic mRNA surveillance system that selectively degrades transcripts with premature termination codons (PTC). Many RNA-binding proteins (RBP) regulate their expression levels by a negative feedback loop, in which RBP binds its own pre-mRNA and causes alternative splicing to introduce a PTC. We present a bioinformatic analysis integrating three data sources, eCLIP assays for a large RBP panel, shRNA inactivation of NMD pathway, and shRNA-depletion of RBPs followed by RNA-seq, to identify novel such autoregulatory feedback loops. We show that RBPs frequently bind their own pre-mRNAs, their exons respond prominently to NMD pathway disruption, and that the responding exons are enriched with nearby eCLIP peaks. We confirm previously proposed models of autoregulation in SRSF7 and U2AF1 genes and present two novel models, in which (i) SFPQ binds its mRNA and promotes switching to an alternative distal 3′-UTR that is targeted by NMD, and (ii) RPS3 binding activates a poison 5′-splice site in its pre-mRNA that leads to a frame shift and degradation by NMD. We also suggest specific splicing events that could be implicated in autoregulatory feedback loops in RBM39, HNRNPM, and U2AF2 genes. The results are available through a UCSC Genome Browser track hub.

    Original languageEnglish
    Pages (from-to)5293-5306
    Number of pages14
    JournalNucleic Acids Research
    Volume47
    Issue number10
    DOIs
    Publication statusPublished - 2019

    Fingerprint

    Dive into the research topics of 'Integrative transcriptomic analysis suggests new autoregulatory splicing events coupled with nonsense-mediated mRNA decay'. Together they form a unique fingerprint.

    Cite this