The dual role of N6-methyladenosine on mouse maternal RNAs and 2-cell specific RNAs revealed by ULI-MeRIP sequencing

N 6 -methyladenosine (m 6 A) and its regulatory components play critical roles in various developmental processes in mammals( 1-5 ). However, the landscape and function of m 6 A in the maternal-to-zygotic transition (MZT) remain unclear due to limited materials. Here, by developing an ultralow-input MeRIP-seq method, we revealed the dynamics of the m 6 A RNA methylome during the MZT process in mice. We found that more than 1/3 maternal decay and 2/3 zygotic mRNAs were modified by m 6 A. Moreover, m 6 As are highly enriched in the RNA of transposable elements MTA and MERVL, which are highly expressed in oocytes and 2-cell embryos, respectively. Notably, maternal depletion of Kiaa1429 , a component of the m 6 A methyltransferase complex, leads to a reduced abundance of m 6 A-marked maternal RNAs, including both genes and MTA, in GV oocytes, indicating m 6 A-dependent regulation of RNA stability in oocytes. Interestingly, when the writers were depleted, some m 6 A-marked 2-cell specific RNAs, including Zscan4 and MERVL, appeared normal at the 2-cell stage but failed to be decayed at later stages, suggesting that m 6 A regulates the clearance of these transcripts. Together, our study uncovered that m 6 As function in context-specific manners during MZT, which ensures the transcriptome stability of oocytes and regulates the stage specificity of zygotic transcripts after fertilization. One Sentence Summary m 6 A RNA methylation stabilizes the maternal RNAs in mouse oocytes and degrades the 2-cell specific RNAs in the cleavage-stage embryos.