Project description: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 PPARG 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 PPARG mediated regulation of a specific transcriptional program, including the lipolytic enzymes ATGL and 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.
Project description: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 PPARG 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 PPARG mediated regulation of a specific transcriptional program, including the lipolytic enzymes ATGL and 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.
Project description:Enhancer-promoter (E-P) interactions regulate transcription for cell fate determination. However, the regulatory mechanisms of E-P interactions remain elusive. Here, a chromatin interaction-based proteomics approach, LoopID, was developed to profile the proteins at certain E-P anchors, which were termed looposome. Histone demethylase JMJD2, a key looposome component, can regulate E-P interactions and looposome in a catalytic-independent manner through forming biomolecular condensates. Furthermore, a system to engineer E-P interactions was introduced by assembling JMJD2 condensates at certain genomic loci, enabling the construction of cell-type specific E-P interactions to promote cellular reprogramming into pluripotent or 2-cell-like cells. Our findings reveal a non-canonical function of histone demethylase in regulating chromatin organization and provide a strategy for regulating cell fate transitions through E-P interactions.