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Regulation of mRNA abundance by polypyrimidine tract-binding protein-controlled alternate 5' splice site choice.
PLoS Genet. 2014 Nov; 10(11):e1004771.PG

Abstract

Alternative splicing (AS) provides a potent mechanism for increasing protein diversity and modulating gene expression levels. How alternate splice sites are selected by the splicing machinery and how AS is integrated into gene regulation networks remain important questions of eukaryotic biology. Here we report that polypyrimidine tract-binding protein 1 (Ptbp1/PTB/hnRNP-I) controls alternate 5' and 3' splice site (5'ss and 3'ss) usage in a large set of mammalian transcripts. A top scoring event identified by our analysis was the choice between competing upstream and downstream 5'ss (u5'ss and d5'ss) in the exon 18 of the Hps1 gene. Hps1 is essential for proper biogenesis of lysosome-related organelles and loss of its function leads to a disease called type 1 Hermansky-Pudlak Syndrome (HPS). We show that Ptbp1 promotes preferential utilization of the u5'ss giving rise to stable mRNAs encoding a full-length Hps1 protein, whereas bias towards d5'ss triggered by Ptbp1 down-regulation generates transcripts susceptible to nonsense-mediated decay (NMD). We further demonstrate that Ptbp1 binds to pyrimidine-rich sequences between the u5'ss and d5'ss and activates the former site rather than repressing the latter. Consistent with this mechanism, u5'ss is intrinsically weaker than d5'ss, with a similar tendency observed for other genes with Ptbp1-induced u5'ss bias. Interestingly, the brain-enriched Ptbp1 paralog Ptbp2/nPTB/brPTB stimulated the u5'ss utilization but with a considerably lower efficiency than Ptbp1. This may account for the tight correlation between Hps1 with Ptbp1 expression levels observed across mammalian tissues. More generally, these data expand our understanding of AS regulation and uncover a post-transcriptional strategy ensuring co-expression of a subordinate gene with its master regulator through an AS-NMD tracking mechanism.

Authors+Show Affiliations

School of Biological Sciences, Nanyang Technological University, Singapore.School of Biological Sciences, Nanyang Technological University, Singapore; MRC Centre for Developmental Neurobiology, King's College London, London, United Kingdom.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25375251

Citation

Hamid, Fursham M., and Eugene V. Makeyev. "Regulation of mRNA Abundance By Polypyrimidine Tract-binding Protein-controlled Alternate 5' Splice Site Choice." PLoS Genetics, vol. 10, no. 11, 2014, pp. e1004771.
Hamid FM, Makeyev EV. Regulation of mRNA abundance by polypyrimidine tract-binding protein-controlled alternate 5' splice site choice. PLoS Genet. 2014;10(11):e1004771.
Hamid, F. M., & Makeyev, E. V. (2014). Regulation of mRNA abundance by polypyrimidine tract-binding protein-controlled alternate 5' splice site choice. PLoS Genetics, 10(11), e1004771. https://doi.org/10.1371/journal.pgen.1004771
Hamid FM, Makeyev EV. Regulation of mRNA Abundance By Polypyrimidine Tract-binding Protein-controlled Alternate 5' Splice Site Choice. PLoS Genet. 2014;10(11):e1004771. PubMed PMID: 25375251.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of mRNA abundance by polypyrimidine tract-binding protein-controlled alternate 5' splice site choice. AU - Hamid,Fursham M, AU - Makeyev,Eugene V, Y1 - 2014/11/06/ PY - 2014/05/26/received PY - 2014/09/22/accepted PY - 2014/11/7/entrez PY - 2014/11/7/pubmed PY - 2015/11/11/medline SP - e1004771 EP - e1004771 JF - PLoS genetics JO - PLoS Genet. VL - 10 IS - 11 N2 - Alternative splicing (AS) provides a potent mechanism for increasing protein diversity and modulating gene expression levels. How alternate splice sites are selected by the splicing machinery and how AS is integrated into gene regulation networks remain important questions of eukaryotic biology. Here we report that polypyrimidine tract-binding protein 1 (Ptbp1/PTB/hnRNP-I) controls alternate 5' and 3' splice site (5'ss and 3'ss) usage in a large set of mammalian transcripts. A top scoring event identified by our analysis was the choice between competing upstream and downstream 5'ss (u5'ss and d5'ss) in the exon 18 of the Hps1 gene. Hps1 is essential for proper biogenesis of lysosome-related organelles and loss of its function leads to a disease called type 1 Hermansky-Pudlak Syndrome (HPS). We show that Ptbp1 promotes preferential utilization of the u5'ss giving rise to stable mRNAs encoding a full-length Hps1 protein, whereas bias towards d5'ss triggered by Ptbp1 down-regulation generates transcripts susceptible to nonsense-mediated decay (NMD). We further demonstrate that Ptbp1 binds to pyrimidine-rich sequences between the u5'ss and d5'ss and activates the former site rather than repressing the latter. Consistent with this mechanism, u5'ss is intrinsically weaker than d5'ss, with a similar tendency observed for other genes with Ptbp1-induced u5'ss bias. Interestingly, the brain-enriched Ptbp1 paralog Ptbp2/nPTB/brPTB stimulated the u5'ss utilization but with a considerably lower efficiency than Ptbp1. This may account for the tight correlation between Hps1 with Ptbp1 expression levels observed across mammalian tissues. More generally, these data expand our understanding of AS regulation and uncover a post-transcriptional strategy ensuring co-expression of a subordinate gene with its master regulator through an AS-NMD tracking mechanism. SN - 1553-7404 UR - https://www.unboundmedicine.com/medline/citation/25375251/Regulation_of_mRNA_abundance_by_polypyrimidine_tract_binding_protein_controlled_alternate_5'_splice_site_choice_ L2 - http://dx.plos.org/10.1371/journal.pgen.1004771 DB - PRIME DP - Unbound Medicine ER -