N6-methyladenosine regulates maternal RNA maintenance in oocytes and timely RNA decay during mouse maternal-to-zygotic transition

Abstract

N⁶-methyladenosine (m⁶A) and its regulatory components play critical roles in various developmental processes in mammals. However, the landscape and function of m⁶A in early embryos remain unclear owing to limited materials. Here we developed a method of ultralow-input m⁶A RNA immunoprecipitation followed by sequencing to reveal the transcriptome-wide m⁶A landscape in mouse oocytes and early embryos and found unique enrichment and dynamics of m⁶A RNA modifications on maternal and zygotic RNAs, including the transcripts of transposable elements MTA and MERVL. Notably, we found that the maternal protein KIAA1429, a component of the m⁶A methyltransferase complex, was essential for m⁶A deposition on maternal mRNAs that undergo decay after zygotic genome activation and MTA transcripts to maintain their stability in oocytes. Interestingly, m⁶A methyltransferases, especially METTL3, deposited m⁶A on mRNAs transcribed during zygotic genome activation and ensured their decay after the two-cell stage, including Zscan4 and MERVL. Together, our findings uncover the essential functions of m⁶A in specific contexts during the maternal-to-zygotic transition, namely ensuring the stability of mRNAs in oocytes and the decay of two-cell-specific transcripts after fertilization.