Acetylation of lysine 49 on Ctnnb1 drives naïve pluripotency in murine stem cells by modulating Nanog function

Naïve pluripotency represents the ground state of mammalian development. A comprehensive understanding of the molecular mechanisms governing its establishment is crucial for elucidating the unique properties of embryonic cells and the regulatory mechanisms controlling cell fate determination. However, the key molecule to robustly achieve naïve pluripotency with minimal manipulation remains unclear. We found that acetylation status of lysine 49 (K49) of Catenin beta-1 (Ctnnb1) plays a critical role in naïve pluripotency of murine stem cells. Deacetylated Ctnnb1 at K49 binds to transcription factor Nanog, impeding its repressor function and thereby promoting differentiation. Remarkably, treatment with IQ1, an inhibitor of interaction between acetyltransferase Ep300 and Ctnnb1, enhances acetylation at K49 of Ctnnb1, enabling establishment and long-term maintenance of embryonic stem cells (ESCs) independently of leukemia inhibitory factor, and also driving complete conversion of epiblast stem cells (EpiSCs) to naïve state. This study reveals the critical role of Ctnnb1 in naïve pluripotency and introduces a novel strategy for its induction and maintenance.