Work

Epitranscriptomic regulation of mRNA stability in pivotal transcription factors modulates the second cell fate decision

Year: 2026

Type: article

Abstract: Embryonic development demands precise coordination of transcriptional and post-transcriptional mechanisms to ensure rapid cell fate transitions, yet the molecular mechanisms by which RNA influences these transitions remain unclear. Here, we observed a global increase in mRNA stability during the blastocyst formation, which precedes rapid lineage specification. Using both in vivo and mouse totipotent blastomere-like cells (TBLCs) or extended pluripotent stem cells (EPSCs) differentiation systems, we demonstrate that this transcriptome-wide stabilization is essential for the second cell fate decision, particularly in the formation of primitive endoderm (PrE). Mechanistically, VIRMA and METTL3, the components of methyltransferase complex (MTC) establish lineage specification by stabilizing the key PrE transcription factors, including Gata6, via the N6-methyladenosine (m6A) reader IGF2BP3. Knocked down of these regulatory proteins or targeted removal of m6A on Gata6, impacted the differentiation of PrE both in vivo and in vitro, and caused defects in blastulation and blastoid formation. Our results demonstrate that m6A-dependent post-transcriptional regulation plays a pivotal role in shaping lineage specification during peri-implantation and provided potential strategies for rescuing developmental defects. Cell fate decisions during early embryonic development require precise regulatory control. Here, the authors show that m6A RNA modification regulates primitive endoderm differentiation by modulating the stability of key transcripts during the second cell fate decision in mouse embryos.

Source: Nature Communications

DOI: 10.1038/s41467-026-72131-2