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bioRxiv · 10.1101/2022.06.01.479622

U1 snRNP-dependent suppression of miRNA biogenesis by alternative intronic polyadenylation in melanoma

Vorlova, S.·Blahetek, G.·Barbieri, R.·Kerstan, Y.·Rosa, A.·Bundalo, M.·Egg, M.·Butt, E.·Henke, E.·Doelken, L.·Houben, R.·Schilling, B.·Fischer, U.·Erhard, F.·Zernecke, A.
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Abstract

Activation of intronic polyadenylation signals results in premature cleavage and polyadenylation (PCPA). The majority of mammalian miRNAs are also located within intronic regions of protein-coding genes and are transcriptionally co-expressed with their host genes. Here we show that U1-dependent PCPA by telescripting dysregulates miRNA biogenesis. When U1 is reduced, miR-211 levels are decreased as a direct consequence of activation of a newly identified alternative intronic polyadenylation signal located upstream of miR-211 within its host gene TRPM1. Various melanoma cell lines revealed decreased U1 levels and a shift from full-length to truncated TRPM1 isoforms with concomitant decreased miR-211 expression. Modulation of TRPM1 alternative polyadenylation (APA) by morpholino oligonucleotides inhibits and potentially restores miR-211 expression to endogenous levels. This mechanism of intronic PCPA and its effects on miRNA biogenesis represents a previously unrecognized layer of gene expression regulation suitable for therapeutic modulation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/479622v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@169c2f1org.highwire.dtl.DTLVardef@7d8f34org.highwire.dtl.DTLVardef@144b9d8org.highwire.dtl.DTLVardef@10523f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Vorlova, S., Blahetek, G., Barbieri, R., Kerstan, Y., Rosa, A., Bundalo, M., Egg, M., Butt, E., Henke, E., Doelken, L., Houben, R., Schilling, B., Fischer, U., Erhard, F., Zernecke, A.. 2022-06-01. U1 snRNP-dependent suppression of miRNA biogenesis by alternative intronic polyadenylation in melanoma. https://doi.org/10.1101/2022.06.01.479622

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