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摘要
Denmark Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a master regulator of adipocyte differentiation, and genome-wide studies indicate that it is involved in the induction of most adipocyte genes. Here we report, for the first time, the acute effects of the synthetic PPAR gamma agonist rosiglitazone on the transcriptional network of PPAR gamma in adipocytes. Treatment with rosiglitazone for 1 hour leads to acute transcriptional activation as well as repression of a number of genes as determined by genome-wide RNA polymerase II occupancy. Unlike what has been shown for many other nuclear receptors, agonist treatment does not lead to major changes in the occurrence of PPAR gamma binding sites. However, rosiglitazone promotes PPAR gamma occupancy at many preexisting sites, and this is paralleled by increased occupancy of the mediator subunit MED1. The increase in PPAR gamma and MED1 binding is correlated with an increase in transcription of nearby genes, indicating that rosiglitazone, in addition to activating the receptor, also promotes its association with DNA, and that this is causally linked to recruitment of mediator and activation of genes. Notably, both rosiglitazone-activated and -repressed genes are induced during adipogenesis. However, rosiglitazone-activated genes are markedly more associated with PPAR gamma than repressed genes and are highly dependent on PPAR gamma for expression in adipocytes. By contrast, repressed genes are associated with the other key adipocyte transcription factor CCAAT-enhancer binding protein alpha (C/EBP alpha), and their expression is more dependent on C/EBP alpha. This suggests that the relative occupancies of PPAR gamma and C/EBP alpha are critical for whether genes will be induced or repressed by PPAR gamma agonist.
- 出版日期2013-9
