The RNA m⁶A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and...

YTHDF2 binds and destabilizes N⁶-methyladenosine (m⁶A)-modified mRNA. The extent to which this branch of m⁶A RNA-regulatory pathway functions in vivo and contributes to mammalian development remains unknown. Here we find that YTHDF2 deficiency is partially permissive in mice and results in female-specific infertility. Using conditional mutagenesis, we demonstrate that YTHDF2 is autonomously required within the germline to produce MII oocytes that are competent to sustain early zygotic development. Oocyte maturation is associated with a wave of maternal RNA degradation, and the resulting relative changes to the MII transcriptome are integral to oocyte quality. The loss of YTHDF2 results in the failure to regulate transcript dosage of a cohort of genes during oocyte maturation, with enrichment observed for the YTHDF2-binding consensus and evidence of m⁶A in these upregulated genes. In summary, the m⁶A-reader YTHDF2 is an intrinsic determinant of mammalian oocyte competence and early zygotic development.