Two target gene activation pathways for orphan ERR nuclear receptors
Two target gene activation pathways for orphan ERR nuclear receptors
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DOI：
10.1038/s41422-022-00774-z
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发表时间：
2023-01-16
期刊：
影响因子：
44.1
通讯作者：
Roeder，Robert G.
中科院分区：
文献类型：
--
作者：
Nakadai，Tomoyoshi;Shimada，Miho;Roeder，Robert G.
雌激素相关受体（ERRα/β/γ）是孤儿核受体，在需要能量的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激活靶基因的潜在机制在很大程度上是未知的。在这里，重建生化检测，表现ERR依赖性转录揭示了两个互补的机制。在DNA模板上，ERR通过ERR DNA结合结构域与起始因子TFIIH的p52亚基的相互作用，仅与一般起始因子的正常补体激活转录。在染色质模板上，ERR的激活依赖于AF 2结构域与细胞特异性共激活因子PGC-1α的相互作用，PGC-1α反过来又募集普遍存在的p300和MED 1/Mediator共激活因子。PGC-1α的这一作用也可以通过其他AF 2相互作用辅激活因子如NCOA 3来实现，NCOA 3显示出选择性地将介体募集到ERRβ和ERRγ。重要的是，组合的遗传和RNA-seq分析确定了TFIIH和AF 2相互作用依赖性途径对于胚胎干细胞中ERRβ/γ选择性基因表达和多能性维持是必不可少的，其中NCOA 3是关键的共激活剂。
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.