Abstract
Timely and selective recruitment of transcription factors to their appropriate DNA-binding sites represents a critical step in regulating gene activation; however, the regulatory strategies underlying each factor's effective recruitment to specific promoter and/or enhancer regions are not fully understood. Here, we identify an unexpected regulatory mechanism by which promoter-specific binding, and therefore function, of peroxisome proliferator-activator receptor γ (PPARγ) in adipocytes requires G protein suppressor 2 (GPS2) to prime the local chromatin environment via inhibition of the ubiquitin ligase RNF8 and stabilization of the H3K9 histone demethylase KDM4A/JMJD2. Integration of genome-wide profiling data indicates that the pioneering activity of GPS2/KDM4A is required for PPARγ-mediated regulation of a specific transcriptional program, including the lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). Hence, our findings reveal that GPS2 exerts a biologically important function in adipose tissue lipid mobilization by directly regulating ubiquitin signaling and indirectly modulating chromatin remodeling to prime selected genes for activation.
Highlights
Members of the nuclear receptor superfamily of transcription factors play critical roles in a variety of developmental processes and in maintaining homeostasis of different organs.Nuclear receptors transcriptional activity is mediated by the recruitment of specific cofactors that are responsible for promoting chromatin remodeling events conducive to gene activation or repression, with the exchange between corepressors and coactivators being a highly regulated process often induced by ligand binding (Glass and Rosenfeld 2000; Perissi and Rosenfeld 2005; Hager et al 2009)
A critical step in the regulation of adipocyte differentiation is an extensive reprogramming of gene expression that includes the activation of a large cohort of adipogenic genes, which are kept under negative regulation in undifferentiated cells
Genome-wide analysis of corepressors binding to DNA during the progression of adipogenesis has revealed a model in which the corepressors SMRT, and NCoR to a lesser extent, function in concert with two DNA-binding partners, namely C/ EBPβ on distal sites and Kaiso on proximal sites, to block adipogenic genes expression in undifferentiated cells (Raghav et al 2012)
Summary
Members of the nuclear receptor superfamily of transcription factors play critical roles in a variety of developmental processes and in maintaining homeostasis of different organs.Nuclear receptors transcriptional activity is mediated by the recruitment of specific cofactors that are responsible for promoting chromatin remodeling events conducive to gene activation or repression, with the exchange between corepressors and coactivators being a highly regulated process often induced by ligand binding (Glass and Rosenfeld 2000; Perissi and Rosenfeld 2005; Hager et al 2009). Genome wide studies of transcription factors binding, histone modifications and chromatin remodeling events have revealed that an epigenomic transition state is initiated within hours of stimulating adipogenesis. This dramatic reorganization of the preadipocyte chromatin landscape includes early transcription factors (C/EBPβ, GR, RXR and STAT5) binding to DNA, transient chromatin opening and changes in histone marks (Lefterova et al 2008; Nielsen et al 2008; Mikkelsen et al 2010; Steger et al 2010; Siersbaek et al 2011). The so-called “adipogenic hotspots” where these changes occur during the very first few hours of differentiation are often found occupied by PPARγ in mature adipocytes, suggesting that early remodeling events could affect PPARγ binding at later stages (Steger et al 2010)
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