N ⁶-methyladenosine enhances post-transcriptional gene regulation by microRNAs

N ⁶-methyladenosine (m⁶A) is the most prevalent modification in eukaryotic messenger RNAs. MicroRNAs (miRNAs) are abundant post-transcriptional regulators of gene expression. Correlation between m⁶A and miRNA-targeting sites has been reported to suggest possible involvement of m⁶A 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 m⁶A and miRNA target binding and regulation.

We found that the level of miRNA-mediated target suppression is significantly enhanced when m⁶A is present on target mRNAs. The evolutionary conservation for miRNA-binding sites with m⁶A modification is significantly higher than that for miRNA-binding sites without modification. These findings suggest functional significance of m⁶A 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 m⁶A modification by itself can destabilize RNA structure, we propose a model in which m⁶A alters local target secondary structure to increase accessibility for efficient binding by Argonaute proteins, leading to enhanced miRNA-mediated regulation.

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