Ivanova Ivayla, Much Christian, Di Giacomo Monica, Azzi Chiara, Morgan Marcos, Moreira Pedro N, Monahan Jack, Carrieri Claudia, Enright Anton J, O'Carroll Dónal
MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK; European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Via Ramarini 32, Monterotondo Scalo 00015, Italy.
European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Via Ramarini 32, Monterotondo Scalo 00015, Italy.
Mol Cell. 2017 Sep 21;67(6):1059-1067.e4. doi: 10.1016/j.molcel.2017.08.003. Epub 2017 Aug 31.
YTHDF2 binds and destabilizes N-methyladenosine (mA)-modified mRNA. The extent to which this branch of mA 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 mA in these upregulated genes. In summary, the mA-reader YTHDF2 is an intrinsic determinant of mammalian oocyte competence and early zygotic development.
YTHDF2与N-甲基腺苷（mA）修饰的mRNA结合并使其不稳定。mA RNA调节途径的这一分支在体内发挥作用并对哺乳动物发育产生影响的程度尚不清楚。在这里，我们发现YTHDF2缺陷在小鼠中部分允许，并导致雌性特异性不育。使用条件诱变，我们证明YTHDF2在生殖系中自主地是产生能够维持早期合子发育的MII卵母细胞所必需的。卵母细胞成熟与一波母体RNA降解相关，并且由此产生的MII转录组的相对变化对于卵母细胞质量是不可或缺的。YTHDF2的缺失导致在卵母细胞成熟过程中未能调节一组基因的转录剂量，在这些上调基因中观察到YTHDF2结合共有序列的富集和mA的证据。总之，mA阅读器YTHDF2是哺乳动物卵母细胞能力和早期合子发育的内在决定因素。
