Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 304, Issue 9, Pages E990-E998Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00608.2012
Keywords
C/EBP beta; G9a; mitotic clonal expansion
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Funding
- National Key Basic Research Project Grants [2011CB910201, 2013CB530601]
- National Natural Science Foundation [81270954, 30870510, 31000603]
- State Key Program of National Natural Science Foundation [31030048]
- Shanghai Rising Star Program [08QA14012]
- Shanghai New Excellent Medicine Talents Program [XYQ2011037]
- Department of Biochemistry and Molecular Biology at Fudan University Shanghai Medical College
- Shanghai Leading Academic Discipline Projects [985III-YFX0302]
- Novartis-Fudan collaboration
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In 3T3-L1 preadipocyte differentiation, the CCAAT/enhancer-binding protein-beta (C/EBP beta) is an important early transcription factor that activates cell cycle genes during mitotic clonal expansion (MCE), sequentially activating peroxisome proliferator-activated receptor-gamma(PPAR gamma) and C/EBP alpha during terminal differentiation. Although C/EBP beta acquires its DNA binding activity via dual phosphorylation at about 12- 16 h postinduction, the expression of PPAR gamma and C/EBP beta is not induced until 36-72 h. The delayed expression of PPAR gamma and C/EBP alpha ensures the progression of MCE, but the mechanism responsible for the delay remains elusive. We provide evidence that G9a, a major euchromatic methyltransferase, is transactivated by C/EBP beta and represses PPAR gamma and C/EBP alpha through H3K9 dimethylation of their promoters during MCE. Inhibitor-or siRNA-mediated G9a downregulation modestly enhances PPAR gamma and C/EBP alpha expression and adipogenesis in 3T3-L1 preadipocytes. Conversely, forced expression of G9a impairs the accumulation of triglycerides. Thus, this study elucidates an epigenetic mechanism for the delayed expression of PPAR gamma and C/ EBP alpha.
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