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Nucleic Acids Res. 2019 Aug 2. pii: gkz664. doi: 10.1093/nar/gkz664. [Epub ahead of print]

Extensive transcriptional responses are co-ordinated by microRNAs as revealed by Exon-Intron Split Analysis (EISA).

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Centre for Cancer Biology, an alliance of SA Pathology and University of South Australia, Adelaide, SA, Australia.
ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
School of Information Technology and Mathematical Sciences, University of South Australia, Mawson Lakes, SA, Australia.
Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
Department of Biochemistry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
School of Medicine, Discipline of Medicine, University of Adelaide, SA, Australia.


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.


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