MicroRNAs and their isomiRs function cooperatively to target common biological pathways

Cloonan, Nicole, Wani, Shivangi, Xu, Qinying, Gu, Jian, Lea, Kristi, Heater, Sheila, Barbacioru, Catalin, Steptoe, Anita L., Martin, Hilary C., Nourbakhsh, Ehsan, Krishnan, Keerthana, Gardiner, Brooke, Wang, Xiaohui, Nones, Katia, Steen, Jason A., Matigan, Nicholas A., Wood, David L., Kassahn, Karin S., Waddell, Nic, Shepherd, Jill, Lee, Clarence, Ichikawa, Jeff, McKernan, Kevin, Bramlett, Kelli, Kuersten, Scott and Grimmond, Sean M. (2011) MicroRNAs and their isomiRs function cooperatively to target common biological pathways. Genome Biology: biology for the post-genomic era, 12 1-20. doi:10.1186/gb-2011-12-12-r126

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Author Cloonan, Nicole
Wani, Shivangi
Xu, Qinying
Gu, Jian
Lea, Kristi
Heater, Sheila
Barbacioru, Catalin
Steptoe, Anita L.
Martin, Hilary C.
Nourbakhsh, Ehsan
Krishnan, Keerthana
Gardiner, Brooke
Wang, Xiaohui
Nones, Katia
Steen, Jason A.
Matigan, Nicholas A.
Wood, David L.
Kassahn, Karin S.
Waddell, Nic
Shepherd, Jill
Lee, Clarence
Ichikawa, Jeff
McKernan, Kevin
Bramlett, Kelli
Kuersten, Scott
Grimmond, Sean M.
Title MicroRNAs and their isomiRs function cooperatively to target common biological pathways
Journal name Genome Biology: biology for the post-genomic era   Check publisher's open access policy
ISSN 1474-760X
Publication date 2011-12-30
Sub-type Article (original research)
DOI 10.1186/gb-2011-12-12-r126
Open Access Status DOI
Volume 12
Start page 1
End page 20
Total pages 20
Place of publication London, United Kingdom
Publisher BioMed Central
Collection year 2012
Language eng
Formatted abstract
Background: Variants of microRNAs (miRNAs), called isomiRs, are commonly reported in deep-sequencing studies; however, the functional significance of these variants remains controversial. Observational studies show that isomiR patterns are non-random, hinting that these molecules could be regulated and therefore functional, although no conclusive biological role has been demonstrated for these molecules.

Results: To assess the biological relevance of isomiRs, we have performed ultra-deep miRNA-seq on ten adult human tissues, and created an analysis pipeline called miRNA-MATE to align, annotate, and analyze miRNAs and their isomiRs. We find that isomiRs share sequence and expression characteristics with canonical miRNAs, and are generally strongly correlated with canonical miRNA expression. A large proportion of isomiRs potentially derive from AGO2 cleavage independent of Dicer. We isolated polyribosome-associated mRNA, captured the mRNA-bound miRNAs, and found that isomiRs and canonical miRNAs are equally associated with translational machinery. Finally, we transfected cells with biotinylated RNA duplexes encoding isomiRs or their canonical counterparts and directly assayed their mRNA targets. These studies allow us to experimentally determine genome-wide mRNA targets, and these experiments showed substantial overlap in functional mRNA networks suppressed by both canonical miRNAs and their isomiRs.

Conclusions: Together, these results find isomiRs to be biologically relevant and functionally cooperative partners of canonical miRNAs that act coordinately to target pathways of functionally related genes. This work exposes the complexity of the miRNA-transcriptome, and helps explain a major miRNA paradox: how specific regulation of biological processes can occur when the specificity of miRNA targeting is mediated by only 6 to 11 nucleotides.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 117 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 129 times in Scopus Article | Citations
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Created: Mon, 30 Jan 2012, 15:37:33 EST by Susan Allen on behalf of Institute for Molecular Bioscience