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Abstract
BackgroundMicroRNAs (miRNAs) are key components in post-transcriptional gene regulation in multicellular organisms. As they control cooperatively a large number of their target genes, they affect the complexity of gene regulation. One of the challenges to understand miRNA-mediated regulation is to identify co-regulating miRNAs that simultaneously regulate their target genes in a network perspective.ResultsWe created miRNA association network by using miRNAs sharing target genes based on sequence complementarity and co-expression patterns of miRNA-target pairs. The degree of association between miRNAs can be assessed by the level of concordance between targets of miRNAs. Cooperatively regulating miRNAs have been identified by network topology-based approach. Cooperativity of miRNAs is evaluated by their shared transcription factors and functional coherence of target genes. Pathway enrichment analysis of target genes in the cooperatively regulating miRNAs revealed the mutually exclusive functional landscape of miRNA cooperativity. In addition, we found that one miRNA in the miRNA association network could be involved in many cooperatively regulating miRNAs in a condition-specific and combinatorial manner. Sequence and structural similarity analysis within miRNA association network showed that pre-miRNA secondary structure may be involved in the expression of mature miRNA's function.ConclusionsOn the system level, we identified cooperatively regulating miRNAs in the miRNA association network. We showed that the secondary structures of pre-miRNAs in cooperatively regulating miRNAs are highly similar. This study demonstrates the potential importance of the secondary structures of pre-miRNAs in both cooperativity and specificity of target genes.
Highlights
MicroRNAs are key components in post-transcriptional gene regulation in multicellular organisms
Considering that most miRNAs exert their functions through interactions with other miRNAs, an understanding of a miRNA network context using both co-expression pattern and the sequence complementarity between miRNAs and mRNAs is essential to discover the cooperative regulation of miRNAs
In miRNA association network (MRAN), a node corresponds to each miRNA that has the significant inverse expression pattern with its targets under each experimental condition (Pearson’s correlation coefficient r < 0), and edges represent target overlap score p value < 0.05
Summary
MicroRNAs (miRNAs) are key components in post-transcriptional gene regulation in multicellular organisms. As they control cooperatively a large number of their target genes, they affect the complexity of gene regulation. Xu et al developed a computational method to identify significant synergistic miRNA pairs via functional co-regulating miRNAs that they jointly regulate [11] Most of these studies did not considered co-expression profiles of mRNAs and miRNAs. Considering that most miRNAs exert their functions through interactions with other miRNAs, an understanding of a miRNA network context using both co-expression pattern and the sequence complementarity between miRNAs and mRNAs is essential to discover the cooperative regulation of miRNAs
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