美国洛克菲勒大学Robert G Roeder研究团队发现孤儿ERR核受体的两种靶基因激活途径。这一研究成果于2023年1月16日在线发表在国际学术期刊《细胞研究》上。

研究人员通过重构的生化分析表明，转录因子依赖转录揭示了两种互补机制。在DNA模板上，雌激素相关受体（ERR）DNA结合域与启动因子TFIIH的p52亚基相互作用，与一般启动因子的正常补体一起激活转录。在染色质模板上，ERR的激活依赖于AF2结构域与细胞特异性辅激活子PGC-1α的相互作用，后者反过来招募泛素p300和MED1/中介体辅激活子。PGC-1α的这一作用也可能由其他af2相互作用的共激活剂（如NCOA3）来实现，NCOA3被证明可以选择性地将中介体招募到ERRβ和ERRγ上。重要的是，结合遗传和RNA-seq分析，TFIIH和AF2相互作用依赖通路都是胚胎干细胞中ERRβ/γ选择性基因表达和多能性维持所需的，其中NCOA3是一个关键的辅激活子。

据介绍，雌激素相关受体（ERRα/β/γ）是孤儿核受体，在能量需求生理过程中发挥作用，以及在发育和干细胞维持中发挥作用，但ERR激活靶基因的机制在很大程度上尚不清楚。

附：英文原文

Title: Two target gene activation pathways for orphan ERR nuclear receptors

Author: Nakadai, Tomoyoshi, Shimada, Miho, Ito, Keiichi, Cevher, Murat Alper, Chu, Chi-Shuen, Kumegawa, Kohei, Maruyama, Reo, Malik, Sohail, Roeder, Robert G

Issue&Volume: 2023-01-16

Abstract: Estrogen-related receptors (ERRα/β/γ) are orphan nuclear receptors that function in energy-demanding physiological processes, as well as in development and stem cell maintenance, but mechanisms underlying target gene activation by ERRs are largely unknown. Here, reconstituted biochemical assays that manifest ERR-dependent transcription have revealed two complementary mechanisms. On DNA templates, ERRs activate transcription with just the normal complement of general initiation factors through an interaction of the ERR DNA-binding domain with the p52 subunit of initiation factor TFIIH. On chromatin templates, activation by ERRs is dependent on AF2 domain interactions with the cell-specific coactivator PGC-1α, which in turn recruits the ubiquitous p300 and MED1/Mediator coactivators. This role of PGC-1α may also be fulfilled by other AF2-interacting coactivators like NCOA3, which is shown to recruit Mediator selectively to ERRβ and ERRγ. Importantly, combined genetic and RNA-seq analyses establish that both the TFIIH and the AF2 interaction-dependent pathways are essential for ERRβ/γ-selective gene expression and pluripotency maintenance in embryonic stem cells in which NCOA3 is a critical coactivator.

DOI: 10.1038/s41422-022-00774-z

Source: https://www.nature.com/articles/s41422-022-00774-z