加拿大多伦多大学Miguel Ramalho-Santos等研究人员合作发现，m⁶A RNA甲基化协调多能性暂停期间的转录休眠。2023年9月7日出版的《自然—细胞生物学》杂志发表了这项成果。

研究人员发现小鼠胚泡和胚胎干（ES）细胞的发育暂停需要Mettl3对N⁶-甲基腺苷（m⁶A）RNA 进行甲基化。Mettl3通过两种相互关联的机制加强转录休眠：（1）它促进全局mRNA失稳；（2）它通过破坏转录扩增因子和癌基因N-Myc的mRNA稳定来抑制全局新生转录。敲除N-Myc可挽救Mettl3^-/-ES细胞的暂停，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是发育暂停期间转录组和表转录组调控之间串联的关键协调者，对成体干细胞休眠和癌症具有影响。

据了解，在不利的环境条件下，各类群的胚胎会进入可逆的发育暂停或休眠状态。这种显著休眠状态的分子机制在很大程度上仍不为人知。

附：英文原文

Title: m6A RNA methylation orchestrates transcriptional dormancy during paused pluripotency

Author: Collignon, Evelyne, Cho, Brandon, Furlan, Giacomo, Fothergill-Robinson, Julie, Martin, Sylvia-Bryn, McClymont, Sarah A., Ross, Robert L., Limbach, Patrick A., Ramalho-Santos, Miguel

Issue&Volume: 2023-09-07

Abstract: 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 N6-methyladenosine (m6A) 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. Collignon et al. report that Mettl3-mediated m6A RNA methylation promotes developmental pausing in embryonic stem cells and blastocysts by establishing transcriptional dormancy.

DOI: 10.1038/s41556-023-01212-x

Source: https://www.nature.com/articles/s41556-023-01212-x