Two target gene activation pathways for orphan ERR nuclear receptors

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...

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Published inCell research Vol. 33; no. 2; pp. 165 - 183
Main Authors Nakadai, Tomoyoshi, Shimada, Miho, Ito, Keiichi, Cevher, Murat Alper, Chu, Chi-Shuen, Kumegawa, Kohei, Maruyama, Reo, Malik, Sohail, Roeder, Robert G
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 01.02.2023
Springer Nature Singapore
Subjects
Chromatin
Deoxyribonucleic acid
DNA
Domains
Embryo cells
Estrogens
Furylfuramide
Gene expression
Genetic analysis
Initiation factors
Kinases
Maintenance
Nuclear receptors
Orphan Nuclear Receptors
Pluripotency
Promoter Regions, Genetic
Receptor mechanisms
Receptors
Receptors, Estrogen - metabolism
Stem cells
Transcriptional Activation
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Summary: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.
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ISSN:1748-7838
1001-0602
1748-7838
DOI:10.1038/s41422-022-00774-z