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Ezh2 Inhibition is Bone-anabolic and Osteoprotective in Skeletally Mature Mice

ABSTRACT: We report genome-wide effects of Ezh2 inhibition (GSK126) in MC3T3 sc4 pre-osteoblasts by ChIP-Seq (H3K27me3) and mRNA-Seq (transcriptome). Treatment of cells for 24 hours with GSK126 suppresses genome-wide H3K27me3, most notably near the transcriptional start sites (TSSs). Genes that exhibit suppression of H3K27me3 near TSSs as a result of GSK126 tend to be up-regulated at the mRNA levels (mRNA-Seq) as well. The mRNA-Seq analysis demonstrates that osteogenic genes are up-regulated after the administration of GSK126. These pro-osteogenic effects are seen 3, 6, and 10 days after the initial GSK126 treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE83506 | GEO | 2016/10/01

SECONDARY ACCESSION(S): PRJNA326208

REPOSITORIES: GEO

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Project description:Osteoporosis is characterized by bone loss, reduced bone strength, and increased fracture risk. Studies have shown that epigenetic mechanisms play a role during bone formation and bone-related disorders, including osteoporosis. However, the contribution of bivalent domains, which are chromatin regions that are co-occupied by the gene activating Histone 3 lysine 4 trimethylation (H3K4me3) and the gene suppressive Histone 3 lysine 27 trimethylation (H3K27me3) marks, has not been elucidated during osteogenesis. Previous work demonstrated that the enhancer of zeste homolog 2 (Ezh2), a histone 3 lysine 27 (H3K27) methyltransferase, suppressed differentiation of osteogenic progenitor cells and that a small molecule inhibitor of Ezh2 (GSK126) enhanced osteogenic commitment of osteoblast progenitors in vitro and bone formation in vivo. Tazemetostat (or EPZ6438) is an Ezh2 inhibitor (iEzh2) that is FDA approved for the treatment of epithelioid sarcoma and might be repurposed to mitigate bone loss. The present study aimed to elucidate mechanisms by which Tazemetostat-mediated H3K27me3 reduction regulates bivalent domain associated enhancers critical for bone formation. Tazemetostat enhanced the expression of bone-related genes (e.g., Runx2-p57, Bglap, Ibsp) as measured by qPCR analysis and stimulated extracellular matrix deposition as revealed by alizarin red staining of cell cultures. Western blotting analysis revealed that Tazemetostat reduced H3K27me3 levels and concomitantly enhanced H3K27Ac, as well as increased protein levels of the osteoblastic master regulator Runx2. Integrative analysis of RNA-seq and ChIP-seq datasets revealed that upregulation of group of genes that are associated with bivalent domains. Importantly, gene ontology analysis showed that genes associated with Wnt, Pth and Hh signaling pathways are enriched within these up-regulated genes. Follow-up mechanistic-based studies revealed that the pro-osteogenic effects induced by Ezh2 inhibition are attenuated by inhibition of Hh signaling and enhanced by disruption of Wnt signaling. Our data demonstrate that the genes controlled by bivalent domains are associated with key osteogenic signaling pathways and are induced upon Ezh2 inhibition and subsequent H3K27me3 reduction. Our data also demonstrate that iEzh2-induced osteogenic differentiation is modulated by Wnt and Hh signaling pathways.

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Ezh2 Inhibition is Bone-anabolic and Osteoprotective in Skeletally Mature Mice

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