PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR {gamma} (PPAR{gamma}) REGULATES GENES INVOLVED IN INSULIN/IGF SIGNALLING AND LIPID METABOLISM DURING ADIPOGENESIS THROUGH FUNCTIONALLY DISTINCT ENHANCER CLASSES [Gene Regulation]

November 28th, 2013 by Oger, F., Dubois-Chevalier, J., Gheeraert, C., Avner, S., Durand, E., Froguel, P., Salbert, G., Staels, B., Lefebvre, P., Eeckhoute, J.

The nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)γ is a transcription factor whose expression is induced during adipogenesis and which is required for acquisition and control of mature adipocyte functions. Indeed, PPARγ induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPARγ also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor (IGF) signalling pathway, which are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, due to stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPARγ utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process.
  • Posted in Journal of Biological Chemistry, Publications
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