Li Zhean, Luo Lingling, Yu Wenxia, Li Ping, Ou Danfeng, Liu Jia, Ma Hanhui, Sun Qinhu, Liang Aibin, Huang Cheng, Chi Tian, Huang Xingxu, Zhang Yu
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
Cell Discov. 2022 Apr 26;8(1):37. doi: 10.1038/s41421-022-00388-0.
Peroxisome proliferator-activated receptor (PPAR)-γ is a key transcription activator controlling adipogenesis and lipid metabolism. PPARγ binds PPAR response elements (PPREs) as the obligate heterodimer with retinoid X receptor (RXR) α, but exactly how PPARγ orchestrates the transcriptional response is unknown. This study demonstrates that PPARγ 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, PPARγ forms nuclear condensates at PPREs sites through phase separation to compartmentalize its heterodimer partner RXRα to initiate PPARγ-specific transcriptional activation. Finally, using an optogenetic approach, the enforced formation of PPARγ/RXRα condensates leads to preferential enrichment at PPREs sites and significantly promotes the expression of PPARγ target genes. These results define a novel mechanism by which PPARγ engages the phase separation principles for efficient and specific transcriptional activation.
过氧化物酶体增殖物激活受体（PPAR）-γ是控制脂肪生成和脂质代谢的关键转录激活因子。PPARγ作为与视黄酸X受体（RXR）α的必需异二聚体结合PPAR反应元件（PPREs），但PPARγ究竟如何协调转录反应尚不清楚。本研究表明，PPARγ在体外形成相分离液滴，在细胞中形成类固体核凝聚物，这一过程有趣地由其具有锌指基序的DNA结合结构域介导。此外，PPARγ通过相分离在PPREs位点形成核凝聚物，将其异二聚体伙伴RXRα分隔开来，从而启动PPARγ特异性转录激活。最后，使用光遗传学方法，PPARγ/RXRα凝聚物的强制形成导致在PPREs位点优先富集，并显著促进PPARγ靶基因的表达。这些结果定义了一种新机制，通过该机制PPARγ利用相分离原理进行高效和特异性转录激活。
