YTHDC1 recognizes METTL16-dependent m⁶A on caRNAs and coordinates cotranscriptional splicing

Area of Science:

• Molecular Biology
• Developmental Biology
• Epitranscriptomics

Background:

• N6-methyladenosine (m6A) RNA modification regulates biological processes.
• The roles of specific m6A writers and readers in RNA metabolism are not fully understood.

Purpose of the Study:

• To investigate the functional specificity of m6A writers and readers in mammalian organogenesis.
• To uncover the molecular mechanisms underlying m6A-mediated RNA regulation during development.

Main Methods:

• Limb organogenesis model in mammals.
• Genetic depletion of m6A writers (METTL16, METTL3) and reader (YTHDC1).
• Analysis of RNA splicing, gene expression, and protein-protein interactions.

Main Results:

• Depletion of YTHDC1 or METTL16, but not METTL3, caused severe limb malformations, indicating functional selectivity.
• YTHDC1 specifically recognizes METTL16-deposited m6A marks on chromatin-associated RNAs.
• YTHDC1 orchestrates cotranscriptional splicing of cell cycle and DNA repair genes, and its loss causes genome-wide transcription arrest.
• Chromatin-bound YTHDC1 recruits splicing factors via liquid-liquid phase separation (LLPS).

Conclusions:

• A specific METTL16-m6A-YTHDC1 axis couples RNA modification with cotranscriptional splicing during mammalian organogenesis.
• This axis is critical for regulating developmental gene expression and ensuring proper limb formation.
• Findings provide molecular insights into epitranscriptomic regulation of developmental decisions.