ECTS2014 Poster Presentations Cell biology: osteoblasts and bone formation (48 abstracts)
Epigenetic modifications and canonical WNT signaling enable direct programming of non-osteogenic cells into osteoblasts
Young-Dan Cho 1 , Won-Joon Yoon 1 , Kyung-Mi Woo 1 , Jeong-Hwa Baek 1 , Gene Lee 1 , Andre J van Wijnen 2 & Hyun-Mo Ryoo 1
1Department of Molecular Genetics, School of Dentistry and DRI, BK21+ Program Seoul National University, Seoul, Republic of Korea; 2Department of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
Mesenchymal cells alter and retain their phenotype during skeletal development through activation or suppression of signaling pathways. For example, we have shown that Wnt3a only stimulates osteoblast differentiation in cells with intrinsic osteogenic potential (e.g., MC3T3-E1 pre-osteoblasts) and not in fat cell precursors or fibroblasts (respectively, 3T3-L1 pre-adipocytes or NIH3T3 fibroblasts). Wnt3a promotes osteogenesis in part by stimulating autocrine production of the osteoinductive ligand Bmp2. Here, we show that the promoter regions of the genes for Bmp2 and the osteoblast marker Alp are epigenetically locked to prevent their expression in non-osteogenic cells. Both genes have conserved CpG islands that exhibit increased CpG methylation, as well as decreased acetylation and increased methylation of histone H3 lysine 9 (H3-K9) specifically in non-osteogenic cells. Treatment of pre-adipocytes or fibroblasts with the CpG demethylating agent 5′-aza-2′-deoxycytidine (5′-aza-dC) or the histone deacetylase inhbitor trichostatin-A (TSA) renders Bmp2 and Alp responsive to Wnt3a. Hence, drug-induced epigenetic activation of Bmp2 gene expression contributes to Wnt3a mediated direct programming (‘trans-differentiation’) of pre-adipocytes or fibroblasts into osteoblasts. We propose that direct conversion of non-osteogenic cells into osteoblastic cell types without inducing pluripotency may improve prospects for novel epigenetic therapies to treat skeletal afflictions.
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