-methyladenosine enhances post-transcriptional gene regulation by microRNAs.

Motivation: -methyladenosine (mA) is the most prevalent modification in eukaryotic messenger RNAs. MicroRNAs (miRNAs) are abundant post-transcriptional regulators of gene expression. Correlation between mA and miRNA-targeting sites has been reported to suggest possible involvement of mA in miRNA-mediated gene regulation. However, it is unknown what the regulatory effects might be. In this study, we performed comprehensive analyses of high-throughput data on mA and miRNA target binding and regulation.

Results: We found that the level of miRNA-mediated target suppression is significantly enhanced when mA is present on target mRNAs. The evolutionary conservation for miRNA-binding sites with mA modification is significantly higher than that for miRNA-binding sites without modification. These findings suggest functional significance of mA modification in post-transcriptional gene regulation by miRNAs. We also found that methylated targets have more stable structure than non-methylated targets, as indicated by significantly higher GC content. Furthermore, miRNA-binding sites that can be potentially methylated are significantly less accessible without methylation than those that do not possess potential methylation sites. Since either RNA-binding proteins or mA modification by itself can destabilize RNA structure, we propose a model in which mA alters local target secondary structure to increase accessibility for efficient binding by Argonaute proteins, leading to enhanced miRNA-mediated regulation.

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