title: Inhibiting DNA methylation switches adipogenesis to osteoblastogenesis by activating Wnt10a.
abstract: Both adipocytes and osteoblasts share the mesodermal lineage that derives from mesenchymal stem cells. Most studies investigating the mechanisms underlying the regulation of adipogenic or osteoblastogenic development focus on transcriptional pathways; little is known about the epigenetic mechanisms in this process. We thus determined the role of 5-aza-2'-deoxycytidine (5-Aza-dC), an inhibitor of DNA methylation, in the lineage determination between adipogenesis and osteoblastogenesis. Inhibiting DNA methylation in 3T3-L1 preadipocytes by 5-Aza-dC significantly inhibited adipogenesis whereas promoted osteoblastogenesis. This dual effect of 5-Aza-dC was associated with up-regulation of Wnt10a, a key factor determining the fate of the mesenchymal lineage towards osteoblasts. Consistently, IWP-2, an inhibitor of Wnt proteins, was found to prevent the anti-adipogenic effect of 5-Aza-dC in 3T3-L1 preadipocytes and block the osteoblastogenic effect of 5-Aza-dC in ST2 mesenchymal stem cell line. Finally, the Wnt10a 5'-region is enriched with CpG sites, whose methylation levels were markedly reduced by 5-Aza-dC. Thus we conclude that inhibiting DNA methylation by 5-Aza-dC mutual-exclusively regulates the lineage determination of adipogenesis and osteoblastogenesis by demethylating Wnt10a gene and upregulating its expression. Our study defines DNA methylation as a novel mechanism underlying adipocyte and bone cell development.
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA, USA.
authors.forename: Yii-Shyuan
authors.initials: YS
authors.lastname: Chen
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA, USA.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA, USA.
authors.forename: Shuping
authors.initials: S
authors.lastname: Kou
authors.affiliation: Department of Molecular &Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Ormond A
authors.initials: OA
authors.lastname: MacDougald
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland, USA.
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.affiliation: Center for Obesity Reversal, Department of Biology, Georgia State University, Atlanta, GA, USA.
authors.forename: Bingzhong
authors.initials: B
authors.lastname: Xue
mesh_terms: D016475:3T3 Cells; D050156:Adipogenesis; D000818:Animals; D002454:Cell Differentiation; D019175:DNA Methylation; D005786:Gene Expression Regulation; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; C484143:Wnt10a protein, mouse