Lunenfeld-Tanenbaum Research Institute and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC) and Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Nat Cell Biol. 2023 Sep;25(9):1279-1289. doi: 10.1038/s41556-023-01212-x. Epub 2023 Sep 7.
Embryos across metazoan lineages can enter reversible states of developmental pausing, or diapause, in response to adverse environmental conditions. The molecular mechanisms that underlie this remarkable dormant state remain largely unknown. Here we show that N-methyladenosine (mA) RNA methylation by Mettl3 is required for developmental pausing in mouse blastocysts and embryonic stem (ES) cells. Mettl3 enforces transcriptional dormancy through two interconnected mechanisms: (1) it promotes global mRNA destabilization and (2) it suppresses global nascent transcription by destabilizing the mRNA of the transcriptional amplifier and oncogene N-Myc, which we identify as a crucial anti-pausing factor. Knockdown of N-Myc rescues pausing in Mettl3 ES cells, and forced demethylation and stabilization of Mycn mRNA in paused wild-type ES cells largely recapitulates the transcriptional defects of Mettl3 ES cells. These findings uncover Mettl3 as a key orchestrator of the crosstalk between transcriptomic and epitranscriptomic regulation during developmental pausing, with implications for dormancy in adult stem cells and cancer.
在多细胞生物谱系中，胚胎可以进入可逆的发育暂停状态，即休眠，以应对不利的环境条件。这种显著的休眠状态的分子机制在很大程度上仍然未知。在这里，我们表明 N6-甲基腺苷（m6A）RNA 甲基化由 Mettl3 介导，是小鼠囊胚和胚胎干细胞（ES 细胞）发育暂停所必需的。Mettl3 通过两种相互关联的机制来维持转录休眠：（1）它促进全局 mRNA 不稳定性，（2）它通过破坏转录放大器和致癌基因 N-Myc 的 mRNA 来抑制全局新生转录，我们将其鉴定为关键的抗暂停因子。N-Myc 的敲低可挽救 Mettl3 ES 细胞中的暂停，而在暂停的野生型 ES 细胞中强制去甲基化和稳定 Mycn mRNA 则在很大程度上重现了 Mettl3 ES 细胞的转录缺陷。这些发现揭示了 Mettl3 作为转录组和表观转录组调控在发育暂停过程中相互作用的关键协调者，这对成年干细胞和癌症中的休眠具有重要意义。
