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Epigenetic modifications and canonical wingless/int-1 class (WNT) signaling enable trans-differentiation of nonosteogenic cells into osteoblasts

Cited 50 time in Web of Science Cited 53 time in Scopus
Authors

Cho, Young-Dan; Yoon, Won-Joon; Kim, Woo-Jin; Woo, Kyung-Mi; Baek, Jeong-Hwa; Lee, Gene; Ku, Young; van Wijnen, Andre J.; Ryoo, Hyun-Mo

Issue Date
2014-07
Publisher
American Society for Biochemistry and Molecular Biology Inc.
Citation
Journal of Biological Chemistry, Vol.289 No.29, pp.20120-20128
Abstract
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 (3T3-L1 pre-adipocytes or NIH3T3 fibroblasts, respectively). 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 nonosteogenic 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 nonosteogenic cells. Treatment of pre-adipocytes or fibroblasts with the CpG-demethylating agent 5' -aza-2' -deoxycytidine or the histone deacetylase inhibitor trichostatin-A renders Bmp2 and Alp responsive to Wnt3a. Hence, drug-induced epigenetic activation of Bmp2 gene expression contributes to Wnt3a-mediated direct trans-differentiation of pre-adipocytes or fibroblasts into osteoblasts. We propose that direct conversion of nonosteogenic cells into osteoblastic cell types without inducing pluripotency may improve prospects for novel epigenetic therapies to treat skeletal afflictions.
ISSN
0021-9258
URI
https://hdl.handle.net/10371/200662
DOI
https://doi.org/10.1074/jbc.M114.558064
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Cho, Young-Dan조영단
(기금)조교수
  • School of Dentistry
  • Department of Dentistry
Research Area Alveolar bone regeneration, Dental implant surface modification, Periomics

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