Peroxisome Proliferator-Activated Receptor γ and C/EBPα Synergistically Activate Key Metabolic Adipocyte Genes by Assisted Loading

Peroxisome proliferator-activated receptor gamma (PPAR gamma) and CCAAT/enhancer binding protein alpha (C/EBP alpha) are key activators of adipogenesis. They mutually induce the expression of each other and have been reported to cooperate in activation of a few adipocyte genes. Recently, genome-wide profiling revealed a high degree of overlap between PPAR gamma and C/EBP alpha binding in adipocytes, suggesting that cooperativeness could be mediated through common binding sites. To directly investigate the interplay between PPAR gamma and C/EBP alpha at shared binding sites, we established a fibroblastic model system in which PPAR gamma and C/EBP alpha can be independently expressed. Using RNA sequencing, we demonstrate that coexpression of PPAR gamma and C/EBP alpha leads to synergistic activation of many key metabolic adipocyte genes. This is associated with extensive C/EBP alpha-mediated reprogramming of PPAR gamma binding and vice versa in the vicinity of these genes, as determined by chromatin immunoprecipitation combined with deep sequencing. Our results indicate that this is at least partly mediated by assisted loading involving chromatin remodeling directed by the leading factor. In conclusion, we report a novel mechanism by which the key adipogenic transcription factors, PPAR gamma and C/EBP alpha, cooperate in activation of the adipocyte gene program.