Epithelial–mesenchymal transition (EMT) has been a subject of intense scrutiny as it facilitates metastasis and alters drug sensitivity. Although EMT-regulatory roles for numerous miRNAs and transcription factors are known, their functions can be difficult to disentangle, in part due to the difficulty in identifying direct miRNA targets from complex datasets and in deciding how to incorporate ‘indirect’ miRNA effects that may, or may not, represent biologically relevant information. To better understand how miRNAs exert effects throughout the transcriptome during EMT, we employed Exon–Intron Split Analysis (EISA), a bioinformatic technique that separates transcriptional and post-transcriptional effects through the separate analysis of RNA-Seq reads mapping to exons and introns. We find that in response to the manipulation of miRNAs, a major effect on gene expression is transcriptional. We also find extensive co-ordination of transcriptional and post-transcriptional regulatory mechanisms during both EMT and mesenchymal to epithelial transition (MET) in response to TGF-β or miR-200c respectively. The prominent transcriptional influence of miRNAs was also observed in other datasets where miRNA levels were perturbed. This work cautions against a narrow approach that is limited to the analysis of direct targets, and demonstrates the utility of EISA to examine complex regulatory networks involving both transcriptional and post-transcriptional mechanisms.
The dynamic transition between epithelial-like and mesenchymal-like cell states has been a focus for extensive investigation for decades, reflective of the importance of Epithelial-Mesenchymal Transition (EMT) through development, in the adult, and the contributing role EMT has to pathologies including metastasis and fibrosis. Not surprisingly, regulation of the complex genetic networks that underlie EMT have been attributed to multiple transcription factors and microRNAs. What is surprising, however, are the sheer number of different regulators (hundreds of transcription factors and microRNAs) for which critical roles have been described. This review seeks not to collate these studies, but to provide a perspective on the fundamental question of whether it is really feasible that so many regulators play important roles and if so, what does this tell us about EMT and more generally, the genetic machinery that controls complex biological processes.
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