The peroxisome proliferator-activated receptor g (PPARg) is a nuclear receptor highly expressed in adipose tissue. It has a crucial role in lipid metabolism and glucose homeostasis. The activity of this transcription factor can be modulated by ligands but also by proteins called coregulators. We wanted to identify new coregulators of PPARg. Several novel potential coregulators of PPARg were identified by a yeast two-hybrid screening of a human adipose tissue cDNA library, with PPARg DE domain as bait. We analyzed two of them: BRG1/Brm-associated factor of 60kDa, subunit c (BAF60c) and Scaffold attachment factor B1 (SAFB1). BAF60c is a component of the chromatin remodeling complex SWI/SNF (mating type switching/sucrose non-fermenting). We identified a second isoform of BAF60c that we called BAF60c2. Both isoforms are ubiquitous nuclear proteins binding to transcription factors and acting as coactivators of nuclear receptors. No role of BAF60c isoforms was demonstrated in adipocyte differentiation as well as cell proliferation. SAFB1 is an ubiquitous nuclear protein interacting with nuclear receptors. SAFB1 inhibits the transcriptional activity of some nuclear receptors such as PPARg and FXRa and is hence a corepressor. The expression level of SAFB1 evolves during adipocyte differentiation, with the highest level coinciding with the clonal expansion phase. We suggest that SAFB1 may influence cell proliferation and differentiation decisions. We identified and characterized novel coregulators of nuclear receptors. The data obtained need to be positioned in a highly complex molecular context. The balance between all the factors is of crucial importance to determine transcriptional activity. Studies in genetically modified mice will help to evaluate the physiological impact of the protagonists. This should give us a better view of the links between nutrient-associated external stimuli and gene regulation and ultimately lead to the elaboration of new therapeutic strategies.
Contributor(s) Written 2004-11 Louis Dallaire
Centre de Recherche, Hôpital Ste-Justine, Montréal, Canada
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