The dynamic landscape and conserved regulation of the m6Am and m6A methylomes during the human and mouse oocyte-to-embryo transition.

N 6-methyladenosine (m6A) and N6, 2'-O-dimethyladenosine (m6Am) are two RNA modifications that play essential roles in diverse RNA metabolic processes and functions. Despite their importance, the dynamic landscapes and regulatory patterns of m6A and m6Am during the oocyte-to-embryo transition (OET) in humans and mice remain elusive. Here, we developed a highly sensitive method, MeLACE-seq, to profile the m6A and m6Am landscapes across human and mouse oocytes to pre-implantation embryos. We reveal that the zygotic genome activation (ZGA) stage serves as a regulatory node where both the m6A and m6Am methylomes undergo dramatic, species-specific changes. Moreover, transcripts marked by m6A and m6Am are generally expressed and translated at higher levels than unmarked transcripts. Additionally, we discovered that m6A modifications are extensively deposited on human retrotransposon RNAs. These m6A marks exhibit a functional shift, showing a positive correlation with elevated retrotransposon RNA levels in pre-ZGA embryos, but a negative correlation with their expression around the ZGA stage. Together, these findings reveal conserved and species-specific regulatory patterns of the epitranscriptome during human and mouse OETs, providing new insights into the roles of RNA modifications in embryogenesis.