H3K27me3 and H3K9me3 as Dual Epigenetic Barriers Restricting Extraembryonic Lineage Potential

In particular, repressive histone modifications display lineage-specific distributions, suggesting a role in constraining cell fate potential. While Polycomb repressive complex 2 (PRC2)-mediated H3K27me3 has been implicated in restricting extraembryonic lineage programs in embryonic stem cells (ESCs), whether additional chromatin mechanisms cooperate to reinforce this barrier remains unclear.

Here, we show that dual inhibition of H3K27me3 and H3K9me2/3 markedly increases extraembryonic plasticity in ESCs by relieving repressive chromatin constraints at lineage-specific gene sets. ESCs under defined conditions with reduced H3K27me3 and H3K9me2/3 exhibit a distinct intermediate cell state with both trophoblast (TE)- and primitive endoderm (PrE)-like features. These cells form blastoids together with naïve ESCs, induce decidua formation, and contribute to the placenta in vivo following morula aggregation, demonstrating functional extraembryonic competence.