title: GPS2/KDM4A pioneering activity regulates promoter-specific recruitment of PPARγ.
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.
authors: Biochemistry Department, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
authors: M Dafne
authors: MD
authors: Cardamone
authors: Department of Medicine, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors: Bogdan
authors: B
authors: Tanasa
authors: Biochemistry Department, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
authors: Michelle
authors: M
authors: Chan
authors: Biochemistry Department, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
authors: Carly T
authors: CT
authors: Cederquist
authors: Biochemistry Department, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
authors: Jaclyn
authors: J
authors: Andricovich
authors: Department of Medicine, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA; Howard Hughes Medical Institute, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors: Michael G
authors: MG
authors: Rosenfeld
authors: Biochemistry Department, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA. Electronic address: vperissi@bu.edu.
authors: Valentina
authors: V
authors: Perissi
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D042002:Chromatin Assembly and Disassembly; D056466:Histone Demethylases / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis / Q000235:genetics; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000217:Acyltransferases
chemical_list: D056466:Histone Demethylases; D047908:Intracellular Signaling Peptides and Proteins; D008049:Lipase; D047495:PPAR gamma; D002787:Sterol Esterase; D044767:Ubiquitin-Protein Ligases; C572597:GPS2 protein, mouse; C560307:JMJD2A protein, mouse; C549817:Rnf8 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases