N6-methyladenosine (m⁶A), the most prevalent internal modification in mammalian mRNA, contributes to post-transcriptional gene regulation, yet how m⁶A presence and modification intensity relate to gene expression during development remains incompletely understood. Here, by integrating m⁶A-seq, RNA-seq, IGF2BP2 RIP-seq, and Ribo-seq data across developmental trajectories of murine heart and liver, we identify a genome-wide presence-dosage pattern of m⁶A-associated gene regulation. m⁶A-modified transcripts generally show higher baseline expression than unmodified transcripts, whereas increasing modification intensity within m⁶A-modified transcripts is associated with reduced transcript abundance. This dual pattern is linked to the binding behavior of the m⁶A reader IGF2BP2: IGF2BP2 occupancy is enriched on m⁶A-modified transcripts but decreases with higher methylation intensity. Structural equation modeling further supports layered associations among m⁶A status, IGF2BP2 binding, transcript abundance, and ribosome occupancy. Regional analysis of m⁶A peaks also suggests position-dependent relationships with translation efficiency, with 3′ UTR m⁶A associated with higher TE and CDS m⁶A associated with lower TE. Together, our study provides a quantitative multi-omic framework for understanding how m⁶A presence and dosage are associated with gene expression and translation during tissue development, and suggests IGF2BP2 binding as a potential mediator of these relationships.
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Liu et al. (2026) studied this question.
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