PPARγ phase separates with RXRα at PPREs to regulate target gene expression

Peroxisome proliferator-activated receptor (PPAR)-gamma is a key transcription activator controlling adipogenesis and lipid metabolism. PPAR gamma binds PPAR response elements (PPREs) as the obligate heterodimer with retinoid X receptor (RXR) alpha, but exactly how PPAR gamma orchestrates the transcriptional response is unknown. This study demonstrates that PPAR gamma forms phase-separated droplets in vitro and solid-like nuclear condensates in cell, which is intriguingly mediated by its DNA binding domain characterized by the zinc finger motif. Furthermore, PPAR gamma forms nuclear condensates at PPREs sites through phase separation to compartmentalize its heterodimer partner RXR alpha to initiate PPAR gamma-specific transcriptional activation. Finally, using an optogenetic approach, the enforced formation of PPAR gamma/RXR alpha condensates leads to preferential enrichment at PPREs sites and significantly promotes the expression of PPAR gamma target genes. These results define a novel mechanism by which PPAR gamma engages the phase separation principles for efficient and specific transcriptional activation.

Automated summary

This study reveals the mechanism of PPAR gamma in forming droplets and nuclear condensates, and demonstrates how PPAR gamma utilizes phase separation principles for transcriptional activation. PPAR gamma specifically forms nuclear condensates at PPREs sites, regulating adipogenesis and lipid metabolism.