GPS2/KDM4A Pioneering Activity Regulates Promoter-Specific Recruitment of PPARγ

• PPARγ binding to promoters depends on H3K9 demethylase KDM4A
• GPS2 stabilizes KDM4A on target promoters by inhibiting Ubc13/RNF8 ubiquitination
• Genome-wide studies reveal a specific program regulated by GPS2/KDM4A
• Rate-limiting lipolysis enzymes ATGL and HSL are regulated by GPS2/KDM4A/PPARγ

SummaryTimely 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.

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