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Cell Syst. 2018 Jul 25;7(1):77-91.e7. doi: 10.1016/j.cels.2018.05.019. Epub 2018 Jul 11.

Combinatorial Targeting by MicroRNAs Co-ordinates Post-transcriptional Control of EMT.

Author information

1
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
2
Centre for Cancer Biology, an Alliance of SA Pathology and University of South Australia, North Terrace, Adelaide, SA 5000, Australia; Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia.
3
Centre for Cancer Biology, an Alliance of SA Pathology and University of South Australia, North Terrace, Adelaide, SA 5000, Australia.
4
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; The University of Melbourne Department of Surgery, St. Vincent's Hospital, Fitzroy, VIC 3065, Australia.
5
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
6
Systems Biology Laboratory, University of Melbourne, Parkville, VIC 3010, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science, Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia; School of Mathematics and Statistics, University of Melbourne, Parkville, VIC 3010, Australia.
7
Centre for Cancer Biology, an Alliance of SA Pathology and University of South Australia, North Terrace, Adelaide, SA 5000, Australia; Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia. Electronic address: cameron.bracken@sa.gov.au.
8
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Biochemistry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: davis.m@wehi.edu.au.

Abstract

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, functioning in part by facilitating the degradation of target mRNAs. They have an established role in controlling epithelial-mesenchymal transition (EMT), a reversible phenotypic program underlying normal and pathological processes. Many studies demonstrate the role of individual miRNAs using overexpression at levels greatly exceeding physiological abundance. This can influence transcripts with relatively poor targeting and may in part explain why over 130 different miRNAs are directly implicated as EMT regulators. Analyzing a human mammary cell model of EMT we found evidence that a set of miRNAs, including the miR-200 and miR-182/183 family members, co-operate in post-transcriptional regulation, both reinforcing and buffering transcriptional output. Investigating this, we demonstrate that combinatorial treatment altered cellular phenotype with miRNA concentrations much closer to endogenous levels and with less off-target effects. This suggests that co-operative targeting by miRNAs is important for their physiological function and future work classifying miRNAs should consider such combinatorial effects.

KEYWORDS:

epithelial-mesenchymal transition; exon-intron split analysis; microRNA; post-transcriptional regulation; transforming growth factor β

PMID:
30007539
DOI:
10.1016/j.cels.2018.05.019
[Indexed for MEDLINE]
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