Talk abstracts
Talk on Saturday 12:35-12:55pm submitted by Heidi Dvinge
Regulation of human alternative splicing by the spliceosomal small nuclear RNAs
Heidi Dvinge (UW-Madison), Robert Bradley (Fred Hutchinson Cancer Research Center)
Abstract:
Alternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing the trans-acting regulatory proteins that control alternative splicing in both healthy and malignant cells has therefore been the focus of much research. Recent work has established that even core protein components of the spliceosome, which are required for splicing to proceed, can nonetheless contribute to splicing regulation by modulating splice site choice. We here demonstrate that the RNA components of the spliceosome likewise influence alternative splicing decisions and contribute to the establishment of global splicing programs. Although these small nuclear RNAs (snRNAs), termed U1, U2, U4, U5, and U6 snRNA, are present in equal stoichiometry within the spliceosome, we found that their relative levels vary by an order of magnitude across tissues, and between normal and malignant cells. Physiologically relevant perturbation of individual snRNAs drove widespread gene-specific differences in alternative splicing, but not transcriptome-wide splicing failure. Our data indicate that endogenous variation in snRNA levels confers regulatory capacity on these RNAs. snRNAs thereby play an unexpectedly complex role in establishing global splicing programs, in addition to their well-characterized roles in basal splicing catalysis. Genes that were particularly sensitive to variations in snRNA abundance in a breast cancer cell line model were likewise preferentially mis-spliced within a clinically diverse cohort of invasive breast ductal carcinomas. As aberrant mRNA splicing is prevalent in many solid and liquid tumors, we propose that a full understanding of dysregulated pre-mRNA processing in cancers requires study of the RNA as well as protein components of the splicing machinery.
Keywords: snRNA, splicing, regulation