During bone marrow stromal cell (BMSC) differentiation, both Wnt signaling and the development of a rigid cytoskeleton promote commitment to the osteoblastic over adipogenic lineage. β‐catenin plays a critical role in the Wnt signaling pathway to facilitate downstream effects on gene expression. We show that β‐catenin was additive with cytoskeletal signals to prevent adipogenesis, and β‐catenin knockdown promoted adipogenesis even when the actin cytoskeleton was depolymerized. β‐catenin also prevented osteoblast commitment in a cytoskeletal‐independent manner, with β‐catenin knockdown enhancing lineage commitment. Chromatin immunoprecipitation (ChIP)‐sequencing demonstrated binding of β‐catenin to the promoter of enhancer of zeste homolog 2 (EZH2), a key component of the polycomb repressive complex 2 (PRC2) complex that catalyzes histone methylation. Knockdown of β‐catenin reduced EZH2 protein levels and decreased methylated histone 3 (H3K27me3) at osteogenic loci. Further, when EZH2 was inhibited, β‐catenin's anti‐differentiation effects were lost. These results indicate that regulating EZH2 activity is key to β‐catenin's effects on BMSCs to preserve multipotentiality. © 2020 American Society for Bone and Mineral Research.

中文翻译：

---

β-连环蛋白通过激活 EZH2 保持小鼠骨髓基质细胞的干状态。

在骨髓基质细胞 (BMSC) 分化过程中，Wnt 信号传导和刚性细胞骨架的发育都促进了对成骨细胞的承诺，而不是成脂谱系。β-连环蛋白在 Wnt 信号通路中发挥关键作用，以促进对基因表达的下游影响。我们表明，β-连环蛋白与细胞骨架信号相加以防止脂肪生成，即使肌动蛋白细胞骨架解聚，β-连环蛋白敲低也能促进脂肪生成。β-连环蛋白还以不依赖于细胞骨架的方式阻止成骨细胞定型，β-连环蛋白敲低增强了谱系定型。染色质免疫沉淀 (ChIP) 测序显示 β-连环蛋白与 zeste 同源物 2 (EZH2) 增强子的启动子结合，催化组蛋白甲基化的多梳抑制复合物 2 (PRC2) 复合物的关键成分。β-连环蛋白的敲除降低了 EZH2 蛋白水平并降低了成骨基因座的甲基化组蛋白 3 (H3K27me3)。此外，当 EZH2 被抑制时，β-连环蛋白的抗分化作用丧失。这些结果表明，调节 EZH2 活性是 β-catenin 作用于 BMSCs 以保持多能性的关键。© 2020 美国骨与矿物研究学会。