Abstract
Classical microRNA (miRNA) has been so far believed as a single sequence, but it indeed contains multiple miRNA isoforms (isomiR) with various sequences and expression patterns. It is not clear whether these diverse isomiRs have potential relationships and whether they contribute to miRNA:mRNA interactions. Here, we aimed to reveal the potential evolutionary and functional relationships of multiple isomiRs based on let-7 and miR-10 gene families that are prone to clustering together on chromosomes. Multiple isomiRs within gene families showed similar functions to their canonical miRNAs, indicating selection of the predominant sequence. IsomiRs containing novel seed regions showed increased/decreased biological function depending on whether they had more/less specific target mRNAs than their annotated seed. Few gene ontology(GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were shared among the target genes of the annotated seeds and the novel seeds. Various let-7 isomiRs with novel seed regions may cause opposing drug responses despite the fact that they are generated from the same miRNA locus and have highly similar sequences. IsomiRs, especially the dominant isomiRs with shifted seeds, may disturb the coding-non-coding RNA regulatory network. These findings provide insight into the multiple isomiRs and isomiR-mediated control of gene expression in the pathogenesis of cancer.
Highlights
The results showed that isomiRs from the let-7 gene family were expressed relatively uniformly across the cancer types
Our analysis showed that some isomiRs contained novel seed regions that arose via seed shifting events such as alternative and imprecise cleavage during the miRNA maturation process
We found that increases and decreases in the expression of annotated let-7a-5p had no significant impact (p = 0.8602) on the survival of colon adenocarcinoma (COAD) patients
Summary
MicroRNA (miRNA, about 22-nt) plays important regulatory roles in multiple biological processes by negatively regulating gene expression at the transcriptional or posttranscriptional levels [1,2]. These small non-coding RNA molecules are promising biomarkers for the diagnosis of cancer. An increasing number of studies suggest that there are multiple varieties of miRNAs, termed isomiRs, which have divergent sequences and expression patterns These diverse miRNA isoforms can be generated by nucleotidyl transferases, RNA editing during the miRNA maturation process [3], which simultaneously leads to sequence variation (especially at the 3ʹ end) and complex small RNA and mRNA interactions.
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