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    MicroRNAs and their isomiRs function cooperatively to target common biological pathways

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    219
    Author
    Cloonan, N; Wani, S; Xu, Q; Gu, J; Lea, K; Heater, S; Barbacioru, C; Steptoe, AL; Martin, HC; Nourbakhsh, E; ...
    Date
    2011-01-01
    Source Title
    Genome Biology
    Publisher
    BMC
    University of Melbourne Author/s
    Grimmond, Sean
    Affiliation
    Centre for Cancer Research
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Cloonan, N., Wani, S., Xu, Q., Gu, J., Lea, K., Heater, S., Barbacioru, C., Steptoe, A. L., Martin, H. C., Nourbakhsh, E., Krishnan, K., Gardiner, B., Wang, X., Nones, K., Steen, J. A., Matigian, N. A., Wood, D. L., Kassahn, K. S., Waddell, N. ,... Grimmond, S. M. (2011). MicroRNAs and their isomiRs function cooperatively to target common biological pathways. GENOME BIOLOGY, 12 (12), https://doi.org/10.1186/gb-2011-12-12-r126.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/260130
    DOI
    10.1186/gb-2011-12-12-r126
    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.

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