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Abstract
Previous studies have shown that CCAAT/enhancer-binding protein α (C/EBPα) plays a very important role during adipocyte terminal differentiation and that AP-2α (activator protein 2α) acts as a repressor to delay the expression of C/EBPα. However, the mechanisms by which AP-2α prevents the expression of C/EBPα are not fully understood. Here, we present evidence that Suv39h1, a histone H3 lysine 9 (H3K9)-specific trimethyltransferase, and G9a, a euchromatic methyltransferase, both interact with AP-2α and enhance AP-2α-mediated transcriptional repression of C/EBPα. Interestingly, we discovered that G9a mediates dimethylation of H3K9, thus providing the substrate, which is methylated by Suv39h1, to H3K9me3 on the C/EBPα promoter. The expression level of AP-2α was consistent with enrichment of H3K9me2 and H3K9me3 on the C/EBPα promoter in 3T3-L1 preadipocytes. Knockdown of Suv39h markedly increased C/EBPα expression and promoted adipogenesis. Conversely, ectopic expression of Suv39h1 delayed C/EBPα expression and impaired the accumulation of triglyceride, while simultaneous knockdown of AP-2α or G9a partially rescued this process. These findings indicate that Suv39h1 enhances AP-2α-mediated transcriptional repression of C/EBPα in an epigenetic manner and further inhibits adipocyte differentiation.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00070-14.
ACKNOWLEDGMENTS
This work was supported by National Key Basic Research Project grants (2011CB910201 to Q. Q. Tang and 2013CB530601 and 2011CBA01103 to X. Li), National Natural Science Foundation grants (81270954 and 30870510 to X. Li), the National Natural Science Foundation of China (31030048 and 81390350 to Q. Q. Tang), the Shanghai Rising Star Program (13QH1400800 to X. Li), and the Shanghai New Excellent Medicine Talents Program (XYQ2011037 to X. Li). The Department of Biochemistry and Molecular Biology at Fudan University Shanghai Medical College is supported by Shanghai Leading Academic Discipline Project B110 and 985 Project 985III-YFX0302.