Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Emeritus Laboratory Rolf Kemler, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
University of Zurich, Institute of Anatomy, 8057 Zurich, Switzerland.
Cell Rep. 2017 Mar 21;18(12):2815-2824. doi: 10.1016/j.celrep.2017.02.076.
Wnt/β-catenin signaling is required for embryonic stem cell (ESC) pluripotency by inducing mesodermal differentiation and inhibiting neuronal differentiation; however, how β-catenin counter-regulates these differentiation pathways is unknown. Here, we show that lysine 49 (K49) of β-catenin is trimethylated (β-catMe3) by Ezh2 or acetylated (β-catAc) by Cbp. Significantly, β-catMe3 acts as a transcriptional co-repressor of the neuronal differentiation genes sox1 and sox3, whereas β-catAc acts as a transcriptional co-activator of the key mesodermal differentiation gene t-brachyury (t-bra). Furthermore, β-catMe3 and β-catAc are alternatively enriched on repressed or activated genes, respectively, during ESC and adult stem cell differentiation into neuronal or mesodermal progenitor cell lineages. Importantly, expression of a β-catenin K49A mutant results in major defects in ESC differentiation. We conclude that β-catenin K49 trimethylation and acetylation are key elements in regulating ESC pluripotency and differentiation potential.
Wnt/β-catenin 信号通路通过诱导中胚层分化和抑制神经元分化来维持胚胎干细胞（ESC）的多能性；然而，β-catenin 如何反向调节这些分化途径尚不清楚。在这里，我们表明β-catenin 的赖氨酸 49（K49）被 Ezh2 三甲基化（β-catMe3）或 Cbp 乙酰化（β-catAc）。重要的是，β-catMe3 作为神经元分化基因 sox1 和 sox3 的转录共抑制因子起作用，而 β-catAc 作为关键中胚层分化基因 t-brachyury（t-bra）的转录共激活因子起作用。此外，在 ESC 和成年干细胞分化为神经元或中胚层祖细胞谱系的过程中，β-catMe3 和 β-catAc 分别在受抑制或激活的基因上选择性富集。重要的是，β-catenin K49A 突变体的表达导致 ESC 分化的主要缺陷。我们得出结论，β-catenin K49 三甲基化和乙酰化是调节 ESC 多能性和分化潜能的关键因素。
