Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Chey Institute for Advanced Studies, Seoul 06141, Republic of Korea.
Cell Rep. 2020 Dec 29;33(13):108598. doi: 10.1016/j.celrep.2020.108598.
During the maternal-to-zygotic transition (MZT), multiple mechanisms precisely control massive decay of maternal mRNAs. N-methyladenosine (mA) is known to regulate mRNA decay, yet how this modification promotes maternal transcript degradation remains unclear. Here, we find that mA promotes maternal mRNA deadenylation. Yet, genetic loss of mA readers Ythdf2 and Ythdf3 did not impact global maternal mRNA clearance, zygotic genome activation, or the onset of gastrulation, challenging the view that Ythdf2 alone is critical to developmental timing. We reveal that Ythdf proteins function redundantly during zebrafish oogenesis and development, as double Ythdf2 and Ythdf3 deletion prevented female gonad formation and triple Ythdf mutants were lethal. Finally, we show that the microRNA miR-430 functions additively with methylation to promote degradation of common transcript targets. Together these findings reveal that mA facilitates maternal mRNA deadenylation and that multiple pathways and readers act in concert to mediate these effects of methylation on RNA stability.
在母源到合子的转变（MZT）期间，多种机制精确地控制着母体 mRNA 的大量降解。N6-甲基腺苷（mA）已知可调节 mRNA 降解，但这种修饰如何促进母体转录本的降解尚不清楚。在这里，我们发现 mA 促进母体 mRNA 的去腺苷酸化。然而，mA 读码器 Ythdf2 和 Ythdf3 的遗传缺失并没有影响全局母体 mRNA 的清除、合子基因组激活或原肠胚形成的开始，这对 Ythdf2 单独对发育时间至关重要的观点提出了挑战。我们揭示了 Ythdf 蛋白在斑马鱼卵子发生和发育过程中具有冗余功能，因为双 Ythdf2 和 Ythdf3 缺失阻止了雌性性腺的形成，而三重 Ythdf 突变体是致命的。最后，我们表明 microRNA miR-430 与甲基化一起发挥作用，促进常见转录靶标物的降解。这些发现共同表明，mA 促进母体 mRNA 的去腺苷酸化，并且多个途径和读码器协同作用以介导甲基化对 RNA 稳定性的这些影响。
