Lin CC et al. (2014), A tri-component conservation strategy reveals h...

XB-ART-51608

PLoS One 2014 Jul 01;97:e103142. doi: 10.1371/journal.pone.0103142.

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A tri-component conservation strategy reveals highly confident microRNA-mRNA interactions and evolution of microRNA regulatory networks.

Lin CC , Mitra R , Zhao Z .

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MicroRNAs are small non-coding RNAs that can regulate expressions of their target genes at the post-transcriptional level. In this study, we propose a tri-component strategy that combines the conservation of microRNAs, homology of mRNA coding regions, and conserved microRNA binding sites in the 3' untranslated regions to discover conserved microRNA-mRNA interactions. To validate the performance of our conservation strategy, we collected the experimentally validated microRNA-mRNA interactions from three databases as the golden standard. We found that the proposed strategy can improve the performance of existing target prediction algorithms by approximately 2-4 fold. In addition, we demonstrated that the proposed strategy could efficiently retain highly confident interactions from the intersection results of the existing algorithms and filter out the possible false positive predictions in the union one. Furthermore, this strategy can facilitate our ability to trace the homologues in different species that are targeted by the same miRNA family because it combines these three features to identify the conserved miRNA-mRNA interactions during evolution. Through an extensive application of the proposed conservation strategy to a study of the miR-1/206 regulatory network, we demonstrate that the target mRNA recruiting process could be associated with expansion of miRNA family during its evolution. We also uncovered the functional evolution of the miR-1/206 regulatory network. In this network, the early targeted genes tend to participate in more general and development-related functions. In summary, the conservation strategy is capable of helping to highlight the highly confident miRNA-mRNA interactions and can be further applied to reveal the evolutionary features of miRNA regulatory network and functions.

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Species referenced: Xenopus
Genes referenced: gnao1

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	Figure 2. The improved performance of the conservation strategy.The performances of the conservation strategy and miRNA target prediction algorithms were evaluated by (A) precision and (B) F-measure. There are three algorithms (TS: TargetScan, MD: miRanda, and MT: MultiMiTar) and three combinations (IntSec: intersection, Union: union, and IntSec(hsa): intersection in humans with unions in other reference species). The results from the original algorithms/combinations were labeled “Predicted” (the left side of the dashed line). The results of the conserved miRNA-mRNA interactions identified by our strategy were labeled “Conserved” (the right side of the dashed line). The numbers along the X-axis indicate the conservation level of the conserved miRNA-mRNA interactions. Both the precision and F-measure are improved after applying the proposed conservation strategy. In two plots (2A and 2B), MD and union nearly overlap.
	Figure 3. Evolutionary analyses of the miR-1/206 family regulatory network.(A) The phylogenetic tree of miR-1/206 family. This tree was drawn by MEGA 5.2.2 (Neighbor-Joining algorithm, 500 bootstrap replications) [42]. Blue: the branch of miR-1 subfamily; light blue: miR-206 subfamily. This tree shows that miR-1 subfamily existed before C. elegans and miR-206 subfamily before D. rerio. (B) The regulatory network of the miR-1/206 family in humans. The miR-1/206 family is represented by an octagon in the center of the network. Circles denote target genes of miR-1/206 in humans. Circle colors denote the most distant species in which the gene was targeted by the miR-1/206 family. The representative enriched functions specific to each species are listed under each species name. (C) The correlation between the Gene Ontology (GO) level of the top 10 enriched functions in miR-1/206 human target genes and the evolutionary distance. Target genes of older species tend to be enriched with more general biological functions, represented by lower levels of GO terms. (Mya: Million Years Ago).
	Figure 1. The tri-component conservation strategy scheme.The scheme of the proposed conservation strategy to identify the conserved miRNA-mRNA interactions is shown. The upper section shows the three major components of miRNA: the regulation-miRNA, mRNA coding region, and 3′ UTR of target mRNA. In the middle section, each color represents a member of one miRNA family. The putative target mRNAs are from homologues in each species. The lower section shows a miRNA-mRNA interaction conserved across k species. We further restricted the conserved miRNA-mRNA interactions that must be detected in both the oldest and youngest species; thus, k is from 2 to n.

References [+] :

Ashburner, Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. 2000, Pubmed