Current Bioinformatics Seminar
2 May 2017
Post-transcriptional regulation in a model of breast cancer epithelial-mesenchymal plasticityMelissa Davis
Epithelial-mesenchymal transition (EMT) is a process whereby cells undergo reversible phenotypic change, losing epithelial characteristics and acquiring mesenchymal attributes. While EMT underlies normal, physiological programs in embryonic tissue development and adult wound healing, it also contributes to cancer progression by facilitating metastasis and altering drug sensitivity. Using a cell model of EMT, we show that miRNAs act as an additional regulatory layer over and above the activity of the transcription factors with which they are closely associated. In this context, miRNAs serve to both enhance expression changes for genes with EMT function, whilst simultaneously reducing transcriptional noise in non-EMT genes. We find that members of the polycistronic miR-200c~141 and miR-183~182 clusters (which are decreased during HMLE cell EMT and are associated with epithelial gene expression in breast cancer patients) co-regulate common targets and pathways to enforce an epithelial phenotype. We demonstrate their combinatorial effects are apparent much closer to endogenous expression levels (and orders of magnitude lower than used in most studies. The low levels of combinatorial miRNAs that are required to exert biological function ameliorate the "off-target" effects on gene expression that are a characteristic of supra-physiologic miRNA manipulation. We propose that the functional effect of co-regulated miRNAs more-accurately reflects the endogenous post-transcriptional regulation of pathways, networks and processes, and illustrates that the post-transcriptional miRNA regulatory network is fundamentally cooperative.