Mar 24, 2020

Hypersilencing of SRRM4 suppresses basal microexon inclusion and promotes tumor growth across cancers

BioRxiv : the Preprint Server for Biology
S. A. HeadLuis Serrano


RNA splicing is widely dysregulated in cancer, frequently due to altered expression or activity of splicing factors. Microexons are extremely small exons (3-27 nucleotides long) that are highly evolutionarily conserved and play critical roles in promoting neuronal differentiation and development. Inclusion of microexons in mRNA transcripts is mediated by the splicing factor SRRM4, whose expression is largely restricted to neural tissues. However, microexons have been largely overlooked in prior analyses of splicing in cancer, as their small size necessitates specialized computational approaches for their detection. Here we demonstrate that despite having low expression in normal non-neural tissues, SRRM4 is hypersilenced in tumors, resulting in the suppression of basal microexon inclusion. Remarkably, SRRM4 is the most consistently silenced splicing factor across all tumor types analyzed, implying a general advantage of microexon downregulation in cancer independent of its tissue of origin. We show that this silencing is favorable for tumor growth, as decreased SRRM4 expression in tumors is correlated with an increase in mitotic gene expression, and upregulation of SRRM4 in cancer cell lines dose-dependently inhibits proliferat...Continue Reading

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