Two target gene activation pathways for orphan ERR nuclear receptors.
Tomoyoshi NakadaiMiho ShimadaKeiichi ItoMurat Alper CevherChi-Shuen ChuKohei KumegawaReo MaruyamaSohail MalikRobert G RoederPublished in: Cell research (2023)
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.
Keyphrases
- single cell
- rna seq
- gene expression
- embryonic stem cells
- dna binding
- transcription factor
- genome wide
- stem cells
- atrial fibrillation
- copy number
- skeletal muscle
- dna methylation
- dna damage
- bone marrow
- cell therapy
- mesenchymal stem cells
- oxidative stress
- circulating tumor
- estrogen receptor
- nucleic acid
- living cells
- circulating tumor cells