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β‐Catenin Preserves the Stem State of Murine Bone Marrow Stromal Cells Through Activation of EZH2
Author(s) -
Sen Buer,
Paradise Christopher R,
Xie Zhihui,
Sankaran Jeyantt,
Uzer Gunes,
Styner Maya,
Meyer Mark,
Dudakovic Amel,
Wijnen Andre J,
Rubin Janet
Publication year - 2020
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.3975
Subject(s) - wnt signaling pathway , microbiology and biotechnology , gene knockdown , chromatin immunoprecipitation , ezh2 , prc2 , osteoblast , catenin , stromal cell , beta catenin , adipogenesis , biology , stem cell , cancer research , histone , chemistry , signal transduction , mesenchymal stem cell , cell culture , gene expression , genetics , gene , promoter , in vitro
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.