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

Area of Science:

• Molecular Biology
• Gene Regulation
• RNA Modifications

Background:

• N6-methyladenosine (m6A) is a dynamic mRNA modification crucial for gene regulation.
• Approximately 35% of m6A marks are found in the coding region (CDS) of mature mRNAs.
• The precise role and decoding features of CDS m6A in translation remain incompletely understood.

Purpose of the Study:

• To investigate the functional significance of m6A modifications within mRNA coding regions.
• To elucidate the impact of CDS m6A on translation elongation and ribosome dynamics.
• To identify the molecular mechanisms and protein factors involved in CDS m6A-mediated gene regulation.

Main Methods:

• Analysis of ribosome pausing at codon-specific sites.
• Experimental manipulation of CDS m6A levels in transcripts.
• Systematic analysis of RNA secondary structures and their resolution.
• Investigating the role of the m6A reader protein YTHDC2 in translation.

Main Results:

• CDS m6A induces codon-specific ribosome pausing.
• Depletion of CDS m6A leads to a significant decrease in translation efficiency.
• CDS m6A positively regulates translation by resolving mRNA secondary structures.
• The elongation-promoting effect of CDS methylation is dependent on the m6A reader YTHDC2.

Conclusions:

• CDS m6A plays a vital physiological role in promoting translation elongation.
• m6A modification in coding regions functions by alleviating mRNA secondary structures.
• The m6A reader YTHDC2 is essential for the elongation-promoting activity of CDS methylation.
• This study reveals distinct, non-overlapping functions of m6A reader proteins in gene expression.