Trimethylation and Acetylation of β-Catenin at Lysine ۴۹ Represent A Key Element in ES Cell Pluripotency

Wnt/β-catenin signaling is required for embryonic stem (ES)cell pluripotency by inducing mesodermal differentiation andinhibiting neuronal differentiation, but how β-catenin counterregulatesthese differentiation pathways is unknown. Here,we show that lysine ۴۹ (K۴۹) of β-catenin is trimethylated(β-catMe۳) by Ezh۲, or acetylated (β-catAc) by Cbp. Significantly,β-catMe۳ acts as a transcriptional co-repressor of theneuronal differentiation genes sox۱ and sox۳, whereas β-catAcacts as a transcriptional co-activator of the key mesodermal differentiationgene t-brachyury (t-bra). Furthermore, β-catMe۳and β-catAc are alternatively enriched on repressed or activatedgenes, respectively, during ES and adult stem cell differentiationinto neuronal or mesodermal progenitor cell lineages. Importantly,expression of a β-catenin K۴۹A mutant results in majordefects in ES cell differentiation. We conclude that β-cateninK۴۹ trimethylation and acetylation are key elements in regulatingES pluripotency and differentiation potential.