Control of cell differentiation occurs through transcriptional mechanisms and through epigenetic modification. Using a chromatin immunoprecipitation-on-chip approach, we performed a genome-wide search for target genes of peroxisome proliferator-activated receptor ␥ (PPAR␥) and its partner protein retinoid X receptor ␣ during adipogenesis. We show that these two receptors target several genes that encode histone lysine methyltransferase SET domain proteins. The histone H4 Lys 20 (H4K20) monomethyltransferase PR-Set7/Setd8 gene is upregulated by PPAR␥ during adipogenesis, and the knockdown of PR-Set7/Setd8 suppressed adipogenesis. Intriguingly, monomethylated H4K20 (H4K20me1) levels are robustly increased toward the end of differentiation. PR-Set7/Setd8 positively regulates the expression of PPAR␥ and its targets through H4K20 monomethylation. Furthermore, the activation of PPAR␥ transcriptional activity leads to the induction of H4K20me1 modification of PPAR␥ and its targets and thereby promotes adipogenesis. We also show that PPAR␥ targets PPAR␥2 and promotes its gene expression through H4K20 monomethylation. Our results connect transcriptional regulation and epigenetic chromatin modulation through H4K20 monomethylation during adipogenesis through a feedback loop.Adipocytes play a central role in energy balance, both as reservoirs of fuel and as endocrine cells, secreting factors that regulate whole-body energy metabolism. Because of the rising incidence of obesity, understanding the adipocyte is increasingly important. The process of adipocyte differentiation represents the extraordinarily coordinated regulation of multiple transcriptional systems that direct multipotent stem-cell precursors to differentiate into fully mature, functionally distinct cell types.The 3T3-L1 preadipocyte cell line has been one of the most well-characterized and widely used models for studying adipocyte differentiation (7). C/EBP␤ and C/EBP␦ are induced very early during differentiation, and these in turn activate two critical proadipogenic transcription factors, peroxisome proliferator-activated receptor ␥ (PPAR␥) and C/EBP␣. PPAR␥ and C/EBP␣ mutually stimulate each other and mediate the transition to the adipocyte phenotype (6,15,32). Recently, a number of transcription factors have been identified as regulators of adipogenesis, including GATA2 (30, 31), the Krüp-pel-like factor (KLF) family (2, 20, 24), and Nr2f2 (35).PPAR␥, a prototypical member of the nuclear receptor superfamily, is activated by natural ligands, such as arachidonic acid metabolites and fatty acid-derived components, and by the insulin-sensitizing thiazolidinedione drugs. In white and brown preadipocyte cell lines, the activation of PPAR␥ by thiazolidinediones results in robust differentiation into adipocytes. The action of PPAR␥ is mediated by two protein isoforms: the widely expressed PPAR␥1 and PPAR␥2, which is restricted to adipose tissue. The expression of each isoform is driven by a specific promoter that confers the distinct tissue-specific expression and...

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