Research Article: Human microRNAs preferentially target genes with intermediate levels of expression and its formation by mammalian evolution

Date Published: May 24, 2018

Publisher: Public Library of Science

Author(s): Hisakazu Iwama, Kiyohito Kato, Hitomi Imachi, Koji Murao, Tsutomu Masaki, Michael Schubert.


MicroRNAs (miRNAs) are short, endogenous RNAs that post-transcriptionally repress mRNAs. Over the course of evolution, many new miRNAs are known to have emerged and added to the existing miRNA repertoires of drosophilids and vertebrates. Despite the large number of miRNAs in existence, the complementary pairing of only ~7 bases between miRNAs and mRNAs is sufficient to induce repression. Thus, miRNA targeting is so widespread that genes coexpressed with a miRNA have evolved to avoid sites that are targeted by the miRNA. Besides this avoidance, little is known about the preferential modes of miRNA targeting. Therefore, to elucidate miRNA targeting preference and avoidance, we evaluated the bias of the number of miRNA targeting occurrences in relation to expression intensities of miRNAs and their coexpressed target mRNAs by surveying transcriptome data from human organs. We found that miRNAs preferentially target genes with intermediate levels of expression, while avoiding highly expressed ones, and that older miRNAs have greater targeting specificity, suggesting that specificity increases during the course of evolution.

Partial Text

MicroRNAs (miRNAs) are ~22-nt endogenous RNAs that modulate mRNAs post-transcriptionally [1–3]. During the course of evolution, miRNAs are documented to have undergone rapid birth-and-death turnovers for drosophilids [4], vertebrates [5], and mammals [6,7]. As a result, many newly-emerged miRNAs have been added to the existing miRNA repertoire. In humans, this was estimated to consist of ~1500 loci annotated in the Ensembl Genes 89 genome assembly [8] or ~1800 in the miRBase 21 database [9], with a lower limit of ~500 loci in the MirGeneDB database, which adopts strict criteria for including miRNAs [10].

We herein demonstrated that miRNAs preferentially target genes of intermediate expression levels while avoiding highly expressed ones, and that this specificity is more pronounced for evolutionarily older miRNAs, suggesting that it has been shaped by evolution. Consistent with the finding that animal miRNAs do not cleave many mRNAs under physiological conditions [22,23], our results showed that the effect of repression by miRNAs is modest or rather often masked by regulatory effects occurring in the opposite direction. Therefore, the observed miRNA targeting specificity is not a direct consequence of the repression.




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