title: Epigenetic programming of Dnmt3a mediated by AP2α is required for granting preadipocyte the ability to differentiate.
abstract: Adipogenesis has an important role in regulating energy homeostasis in mammals. 3T3-L1 preadipocytes have been widely used as an in vitro model for analyzing the molecular mechanism of adipogenesis. Previous reports indicated that the stage of contact inhibition (CI), through which the proliferating cells exit from the cell cycle, was required for granting preadipocyte the ability to differentiate. While this kind of the granting mechanism remains elusive. In the present study, we showed that DNA (cytosine-5) methyltransferase 3a (Dnmt3a) was upregulated at both the mRNA and protein level during the CI stage, and resulted in increasing promoter methylation of adipogenic genes. We further identified that the expression of Activator protein 2α (AP2α), a member of the transcription factor activator protein 2 (AP2) family, was highly correlated with the expression of Dnmt3a during the CI stage. In addition, we showed that AP2α transcriptionally upregulated Dnmt3a by directly binding to its proximal promoter region. Importantly, treatment of 3T3-L1 preadipocytes with AP2α-specific siRNAs inhibited the preadipocyte differentiation in a stage-dependent manner, supporting the conclusion that AP2α has an important role during the CI stage. Furthermore, overexpression of Dnmt3a partially rescued the impairment of adipogenesis induced by AP2α knockdown. Collectively, our findings reveal that AP2α is an essential regulator for granting preadipocyte the ability to differentiate through the upregulation of Dnmt3a expression during the CI stage.
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|School of Life Science and Technology, ShanghaiTech University, Shanghai, China.|School of Life Science, University of Chinese Academy of Sciences, Shanghai,China.
authors.forename: Jiangnan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jianbei
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|School of Life Science and Technology, ShanghaiTech University, Shanghai, China.|Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Wu
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D065150:Cellular Reprogramming / Q000235:genetics*; D003260:Contact Inhibition / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D016678:Genome; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: C000715535:Dnmt3a protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A