m⁶A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2.

Abstract

Dynamic mRNA modification in the form of N⁶-methyladenosine (m⁶A) adds considerable richness and sophistication to gene regulation. The m⁶A mark is asymmetrically distributed along mature mRNAs, with approximately 35% of m⁶A residues located within the coding region (CDS). It has been suggested that methylation in CDS slows down translation elongation. However, neither the decoding feature of endogenous mRNAs nor the physiological significance of CDS m⁶A has been clearly defined. Here, we found that CDS m⁶A leads to ribosome pausing in a codon-specific manner. Unexpectedly, removing CDS m⁶A from these transcripts results in a further decrease of translation. A systemic analysis of RNA structural datasets revealed that CDS m⁶A positively regulates translation by resolving mRNA secondary structures. We further demonstrate that the elongation-promoting effect of CDS methylation requires the RNA helicase-containing m⁶A reader YTHDC2. Our findings established the physiological significance of CDS methylation and uncovered non-overlapping function of m⁶A reader proteins.