Chromatin-bound Mtf2 Restricts Extraembryonic Competence in Naïve Pluripotency [Cut & Tag]

ABSTRACT: The first fate decision of totipotent blastomeres separates embryonic and extraembryonic lineages, giving rise to the inner cell mass (ICM) and trophectoderm (TE). This developmental transition is considered final and irreversible, necessitating extensive gene expression and epigenetic remodeling to ensure its unidirectionality. Here, we identify the PRC2.1 subunit Mtf2 as a critical epigenetic safeguard of this restriction. Although naïve embryonic stem cells (ESCs) display globally high H3K27me3 levels, loss of Mtf2 (M2KO) derepressed TE regulators, increased cellular plasticity, and produced both ICM- and TE-like populations. M2KO cells efficiently converted to expanded-potential states with extraembryonic competence and generated blastoids without TSC supplementation. In contrast, loss of the PRC2.2 subunit Jarid2 did not elicit such effects. Integrated CUT&Tag and transcriptomic profiling revealed that Mtf2 directly represses TE-associated genes in naïve ESCs, which remain active in expanded potential stem cells and M2KO due to reduced Mtf2 binding. These findings establish Mtf2 as an epigenetic barrier that enforces lineage fidelity, stabilizes naïve pluripotency, and restricts extraembryonic competence.

ORGANISM(S): Mus musculus

PROVIDER: GSE306593 | GEO | 2025/12/01

REPOSITORIES: GEO