3'UTR Shortening Potentiates MicroRNA-Based Repression of Pro-differentiation Genes in Proliferating Human Cells

Autor: Moshe Oren, Debora Rosa Bublik, Yonit Hoffman, Reuven Agami, Alejandro Pineiro Ugalde, Tammy Biniashvili, Yitzhak Pilpel, Ran Elkon
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: PLoS Genetics, Vol 12, Iss 2, p e1005879 (2016)
PLoS Genetics
ISSN: 1553-7404
1553-7390
Popis: Most mammalian genes often feature alternative polyadenylation (APA) sites and hence diverse 3’UTR lengths. Proliferating cells were reported to favor APA sites that result in shorter 3’UTRs. One consequence of such shortening is escape of mRNAs from targeting by microRNAs (miRNAs) whose binding sites are eliminated. Such a mechanism might provide proliferation-related genes with an expression gain during normal or cancerous proliferation. Notably, miRNA sites tend to be more active when located near both ends of the 3’UTR compared to those located more centrally. Accordingly, miRNA sites located near the center of the full 3’UTR might become more active upon 3'UTR shortening. To address this conjecture we performed 3' sequencing to determine the 3' ends of all human UTRs in several cell lines. Remarkably, we found that conserved miRNA binding sites are preferentially enriched immediately upstream to APA sites, and this enrichment is more prominent in pro-differentiation/anti-proliferative genes. Binding sites of the miR17-92 cluster, upregulated in rapidly proliferating cells, are particularly enriched just upstream to APA sites, presumably conferring stronger inhibitory activity upon shortening. Thus 3’UTR shortening appears not only to enable escape from inhibition of growth promoting genes but also to potentiate repression of anti-proliferative genes.
Author Summary MicroRNAs (miRNAs) are regulators of gene expression. Typically they recognize a binding site in genes' sequences and exert a repressive effect. This scheme prescribes a regulatory network that determines which gene is regulated by which miRNA. Yet this is a static sequence-based scheme that might not support dynamic changes in network wiring. Can genes become subject to, or be released, from the regulation of a miRNA in a manner that depends on the physiological state of cells? Here we describe such a dynamic mechanism. It is established that miRNA regulation is often more effective when their binding sites reside near the end of the target mRNA or right after the coding sequence STOP codon. Thus, a site distant from the mRNA’s end might be latent as it will not bind efficiently its corresponding miRNA. Yet, in particular physiological states, e.g. cancer or rapidly proliferating cells, mRNA ends tend to become shortened. So far it was suggested that such shortening may serve to release proliferation-favoring genes from miRNA repression by eliminating their binding sites from the mRNA. We propose a mirror image, complementary mechanism that acts upon genes that need to be repressed during proliferation. Specifically, we propose that mRNA shortening can dynamically activate latent repressive miRNA binding sites by bringing the mRNA end close to them. We mapped the ends of all mRNAs in proliferating cells and found that cancer-enriched ends are strikingly positioned closely downstream to a high density of potentially latent binding sites, which are retained in the short mRNA but are now close to the new ends. This may enable such potentially latent miRNA sites to become dynamically activated upon proliferation. Remarkably, this mechanism targets preferentially pro-differentiation and antiproliferative genes, which are often repressed in cancer.
Databáze: OpenAIRE
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