Exon architecture controls mRNA m⁶A suppression and gene expression

Area of Science:

• Molecular Biology
• RNA Biology
• Epigenetics

Background:

• N-methyladenosine (m6A) is the most prevalent mRNA modification, crucial for various cellular functions.
• The precise regulation of m6A deposition across the transcriptome is not fully understood.

Purpose of the Study:

• To investigate the global regulators of m6A specificity.
• To identify factors that prevent m6A deposition in specific transcriptome regions.

Main Methods:

• Utilized a massively parallel assay for m6A (MPm6A) to map m6A modification sites genome-wide.
• Investigated the role of exon junction complexes (EJCs) in m6A regulation.

Main Results:

• Discovered that EJCs act as global suppressors of m6A deposition.
• EJCs protect exon junction-proximal RNA within coding sequences from methylation.
• EJC-mediated m6A suppression influences mRNA stability and is dependent on exon length and position.
• EJC-suppressed methylation sites correlate with EJC-suppressed splice sites, indicating exon architecture's role in RNA accessibility.

Conclusions:

• EJCs are key regulators of m6A specificity, preventing methylation in specific RNA regions.
• Exon architecture plays a significant role in determining the accessibility of mRNA to regulatory complexes like EJCs.
• EJC-mediated m6A suppression is a critical mechanism for controlling mRNA fate and function.