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RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing

Heidi Dvinge, Jamie Guenthoer, Peggy L. Porter, Robert K. Bradley
doi: https://doi.org/10.1101/326983
Heidi Dvinge
1Computational Biology Program, Public Health Sciences Division; Fred Hutchinson Cancer Research Center; Seattle, WA, 98109; USA
2Basic Sciences Division; Fred Hutchinson Cancer Research Center; Seattle, WA, 98109; USA
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  • For correspondence: dvinge@wisc.edu rbradley@fredhutch.org
Jamie Guenthoer
3Human Biology Division; Fred Hutchinson Cancer Research Center; Seattle, WA, 98109; USA
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Peggy L. Porter
3Human Biology Division; Fred Hutchinson Cancer Research Center; Seattle, WA, 98109; USA
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Robert K. Bradley
1Computational Biology Program, Public Health Sciences Division; Fred Hutchinson Cancer Research Center; Seattle, WA, 98109; USA
2Basic Sciences Division; Fred Hutchinson Cancer Research Center; Seattle, WA, 98109; USA
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  • For correspondence: dvinge@wisc.edu rbradley@fredhutch.org
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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 during development, 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. 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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 21, 2018.
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RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing
Heidi Dvinge, Jamie Guenthoer, Peggy L. Porter, Robert K. Bradley
bioRxiv 326983; doi: https://doi.org/10.1101/326983
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RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing
Heidi Dvinge, Jamie Guenthoer, Peggy L. Porter, Robert K. Bradley
bioRxiv 326983; doi: https://doi.org/10.1101/326983

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