Suv39h1 Mediates AP-2α-Dependent Inhibition of C/EBPα Expression during Adipogenesis

Previous studies have shown that CCAAT/enhancer-binding protein alpha (C/EBP alpha) plays a very important role during adipocyte terminal differentiation and that AP-2 alpha (activator protein 2 alpha) acts as a repressor to delay the expression of C/EBP alpha. However, the mechanisms by which AP-2 alpha prevents the expression of C/EBP alpha 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-2 alpha and enhance AP-2 alpha-mediated transcriptional repression of C/EBP alpha. Interestingly, we discovered that G9a mediates dimethylation of H3K9, thus providing the substrate, which is methylated by Suv39h1, to H3K9me3 on the C/EBP alpha promoter. The expression level of AP-2 alpha was consistent with enrichment of H3K9me2 and H3K9me3 on the C/EBP alpha promoter in 3T3-L1 preadipocytes. Knockdown of Suv39h markedly increased C/EBP alpha expression and promoted adipogenesis. Conversely, ectopic expression of Suv39h1 delayed C/EBP alpha expression and impaired the accumulation of triglyceride, while simultaneous knockdown of AP-2 alpha or G9a partially rescued this process. These findings indicate that Suv39h1 enhances AP-2 alpha-mediated transcriptional repression of C/EBP alpha in an epigenetic manner and further inhibits adipocyte differentiation.