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

Ivayla Ivanova, Christian Much, Monica Di Giacomo, Chiara Azzi, Marcos Morgan, Pedro N. Moreira, Jack Monahan, Claudia Carrieri, Anton J. Enright (Lead / Corresponding author), Dónal O'Carroll (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    123 Citations (Scopus)
    129 Downloads (Pure)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)1059-1067.e4
    Number of pages13
    JournalMolecular Cell
    Volume67
    Issue number6
    Early online date31 Aug 2017
    DOIs
    Publication statusPublished - 21 Sep 2017

    Keywords

    • Animals
    • Binding sites
    • Female
    • Fertility
    • Gene expression regulation, Developmental
    • Genotype
    • Infertility, Female
    • Meiosis
    • Mice, Inbred C57BL
    • Mice, Knockout
    • Oocytes
    • Phenotype
    • Protein binding
    • RNA processing, Post-Transcriptional
    • RNA, Messenger
    • RNA-binding proteins
    • Transcription, Genetic
    • Transcriptome
    • Zygote
    • Journal article

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