Regulation of mRNA Abundance by Polypyrimidine Tract-Binding Protein-Controlled Alternate 5′ Splice Site Choice

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Mammalian gene expression is extensively controlled at the post-transcriptional level and understanding of the underlying mechanisms can provide important biomedical insights. Here we identified a number of novel alternate splicing (AS) events where the choice between competing splice sites (ss) is regulated by polypyrimidine tract-binding protein 1 (Ptbp1/PTB/hnRNP-I). A top-scoring event was the choice between alternate upstream and downstream 5′ss (u5′ss and d5′ss) in the Hps1 gene mutated in patients with type 1 Hermansky-Pudlak Syndrome (HPS). Preferential utilization of the u5′ss in the presence of Ptbp1 gives rise to stable mRNAs encoding a full-length Hps1 protein, whereas the d5′ss bias triggered by Ptbp1 down-regulation generates RNA species cleared by nonsense-mediated decay (NMD). We show that Ptbp1 functions in this circuitry by activating the intrinsically weaker u5′ss. Brain-enriched Ptbp1 paralog Ptbp2/nPTB/brPTB stimulated the u5′ss utilization but with a considerably lower efficiency than Ptbp1. We propose that this mechanism accounts for a tight correlation between Hps1 with Ptbp1 expression levels observed in mammalian tissues. Overall, these data expand our understanding of AS regulation and uncover an AS-NMD-mediated tracking mechanism ensuring co-expression of master regulator and its subordinate gene.

Vyšlo v časopise: Regulation of mRNA Abundance by Polypyrimidine Tract-Binding Protein-Controlled Alternate 5′ Splice Site Choice. PLoS Genet 10(11): e32767. doi:10.1371/journal.pgen.1004771
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004771

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