Integrative Omics Analysis Reveals the Importance and Scope of Translational Repression in microRNA-mediated Regulation

MicroRNAs (miRNAs) are key post-transcriptional regulators that inhibit gene expression by promoting mRNA decay and/or suppressing translation. However, the relative contributions of these two mechanisms to gene repression remain controversial. Early studies favor a translational repression-centric scenario, whereas recent large-scale studies suggest a dominant role of mRNA decay in miRNA regulation. Here we generated proteomics data for nine colorectal cancer cell lines and integrated them with matched miRNA and mRNA expression data to infer and characterize miRNA-mediated regulation. Consistent with previous reports, we found that 8mer site, site positioning within 3'UTR, local AU-rich context, and additional 3' pairing could all help boost miRNA-mediated mRNA decay. However, these sequence features were generally not correlated with increased translational repression, except for local AU-rich context. Thus the contribution of translational repression might be underestimated in recent studies in which the analyses were based primarily on the response of genes with canonical 7-8 mer sites in 3'UTRs. Indeed, we found that translational repression was involved in more than half, and played a major role in one-third of all predicted miRNA-target interactions. It was even the predominant contributor to miR-138 mediated regulation, which was further supported by the observation that differential expression of miR-138 in two genetically matched cell lines corresponded to altered protein but not mRNA abundance of most target genes. In addition, our study also provided interesting insights into colon cancer biology such as the possible contributions of miR-138 and miR-141/miR-200c in inducing specific phenotypes of SW480 and RKO cell lines, respectively.