Cell Rep. 2014 Jul 10;8(1):163-76. doi: 10.1016/j.celrep.2014.05.041. Epub 2014 Jun 19.

GPS2/KDM4A pioneering activity regulates promoter-specific recruitment of PPARγ.

Cardamone MD¹, Tanasa B², Chan M¹, Cederquist CT¹, Andricovich J¹, Rosenfeld MG³, Perissi V⁴.

Author information

1: Biochemistry Department, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
2: Department of Medicine, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
3: 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.
4: Biochemistry Department, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA. Electronic address: vperissi@bu.edu.

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.