Epigenetic Regulation of Adipocyte Differentiation by a Rho Guanine Nucleotide Exchange Factor, WGEF

Epigenetic regulation, including DNA methylation, plays an important role in several differentiation processes and possibly in adipocyte differentiation. To search for genes that show methylation change during adipogenesis, genome-wide DNA methylation analysis in insulin-induced adipogenesis of 3T3-L1 preadipocyte cells was performed using a method called microarray-based integrated analysis of methylation by isoschizomers (MIAMI). The MIAMI revealed that Hpa II sites of exon 1 in a Rho guanine nucleotide exchange factor 19 (ARHGEF19; WGEF) gene were demethylated during adipocyte differentiation of 3T3-L1 cells. Deletion of the region containing cytosine-guanine (CpG) sites that showed methylation change suppressed transcriptional activity in the reporter assay, indicating that this region regulates WGEF transcription. WGEF expression in 3T3-L1 cells was reduced during adipocyte differentiation, and high-fat diet-induced obese mice also showed lower expression of WGEF gene than control mice in white adipose tissue. Additionally, forced expression of WGEF in 3T3-L1 cells down-regulated the expression of adipogenic marker genes and inhibited the adipogenic program. This study clarified that adipogenesis was regulated by WGEF expression through DNA methylation change.