N6-methyladenosine modulate second cell fate decision by enhancing mRNA stability of pivotal transcription factors during primitive endoderm development [TBLC_RNAseq]

During second cell fate decisions in pre-implantation embryonic development, upregulated key TFs, including GATA6 and NANOG, drive the differentiation and functional establishment of primitive endoderm (PrE) and epiblast (EPI) cells. However, how the embryo achieves this swift TF upregulation and the precise molecular mechanisms underlying specific TF initiation remain unclear.

In this study, we showed how N6-methyladenosine (m6A) affected embryo and embryoid differentiation. Using two types of extended pluripotent mouse embryonic stem cells with in vivo embryonic and extraembryonic potency-extended pluripotent stem cells (EPSCs) and totipotent blastomere-like cells (TBLCs) alongside mouse embryos, we observed that the m6A writers METTL3 and VIRMA were essential for PrE development. Mechanistically, globally increased mRNA stability occurred during embryo development - mediated by m6A modification.