m6A RNA methylation orchestrates transcriptional dormancy during developmental pausing

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 m6A RNA methylation by Mettl3 is required for developmental pausing in mice by maintaining dormancy of paused embryonic stem cells and blastocysts. Mettl3 enforces transcriptional dormancy via two interconnected mechanisms: i) it promotes global mRNA destabilization and ii) suppresses global nascent transcription by specifically destabilizing the mRNA of the transcriptional amplifier and oncogene N-Myc, which we identify as a critical anti-pausing factor. Our findings reveal Mettl3 as a key orchestrator of the crosstalk between transcriptomic and epitranscriptomic regulation during pausing, with implications for dormancy in stem cells and cancer.