?-Catenin Preserves the Stem State of Murine Bone Marrow Stromal Cells Through Activation of EZH2.

ABSTRACT: 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. ?-catenin plays a critical role in the Wnt signaling pathway to facilitate downstream effects on gene expression. We show that ?-catenin was additive with cytoskeletal signals to prevent adipogenesis, and ?-catenin knockdown promoted adipogenesis even when the actin cytoskeleton was depolymerized. ?-catenin also prevented osteoblast commitment in a cytoskeletal-independent manner, with ?-catenin knockdown enhancing lineage commitment. Chromatin immunoprecipitation (ChIP)-sequencing demonstrated binding of ?-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 ?-catenin reduced EZH2 protein levels and decreased methylated histone 3 (H3K27me3) at osteogenic loci. Further, when EZH2 was inhibited, ?-catenin's anti-differentiation effects were lost. These results indicate that regulating EZH2 activity is key to ?-catenin's effects on BMSCs to preserve multipotentiality. © 2020 American Society for Bone and Mineral Research.

SUBMITTER: Sen B 

PROVIDER: S-EPMC7295671 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature