title: Epigenetic modifications and canonical wingless/int-1 class (WNT) signaling enable trans-differentiation of nonosteogenic cells into osteoblasts.
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.
authors.affiliation: From the Departments of Molecular Genetics and Periodontology, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul 110-749, Korea and.
authors.forename: Young-Dan
authors.initials: YD
authors.lastname: Cho
authors.affiliation: From the Departments of Molecular Genetics and.
authors.forename: Won-Joon
authors.initials: WJ
authors.lastname: Yoon
authors.affiliation: From the Departments of Molecular Genetics and.
authors.forename: Woo-Jin
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: From the Departments of Molecular Genetics and.
authors.forename: Kyung-Mi
authors.initials: KM
authors.lastname: Woo
authors.affiliation: From the Departments of Molecular Genetics and.
authors.forename: Jeong-Hwa
authors.initials: JH
authors.lastname: Baek
authors.affiliation: From the Departments of Molecular Genetics and.
authors.forename: Gene
authors.initials: G
authors.lastname: Lee
authors.affiliation: Periodontology, School of Dentistry and Dental Research Institute, BK21 Program, Seoul National University, Seoul 110-749, Korea and.
authors.forename: Young
authors.initials: Y
authors.lastname: Ku
authors.affiliation: the Departments of Orthopedic Surgery and Biochemistry and of Molecular Biology, Mayo Clinic, Rochester, Minnesota 55902 vanWijnen.Andre@mayo.edu.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: From the Departments of Molecular Genetics and hmryoo@snu.ac.kr.
authors.forename: Hyun-Mo
authors.initials: HM
authors.lastname: Ryoo
mesh_terms: D016475:3T3 Cells; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D054338:Cell Transdifferentiation / Q000235:genetics* / Q000502:physiology*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006657:Histones / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D006657:Histones; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D000469:Alkaline Phosphatase
keywords: Bone Morphogenetic Protein (BMP); Cell Differentiation; Epigenetics; Osteoblast; Wnt Signaling