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Two target gene activation pathways for orphan ERR nuclear receptors
Tomoyoshi Nakadai1,2 , Miho Shimada1,3 , Keiichi Ito1 , Murat Alper Cevher1,4 , Chi-Shuen Chu1 , Kohei Kumegawa5 , Reo Maruyama2 , Sohail Malik1 , Robert G Roeder1,*
1Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USAEstrogen-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.
https://doi.org/10.1038/s41422-022-00774-z
