Deoxyribonucleic Acid Response Element-Dependent Regulation of Transcription by Orphan Nuclear Receptor Estrogen Receptor-Related Receptor γ

The estrogen receptor-related receptor γ (ERRγ/ERR3/NR3B3) is the newest member of the ERR subfamily that also includes ERRα and ERRβ. All three isoforms share a high degree of amino acid identity especially in the DNA binding domain. ERRγ is a constitutively active transcriptional activator that regulates reporter elements driven by steroidogenic factor 1 response element (SF-1RE) and estrogen response element. However, it has the highest potency on a derivative of SF-1RE present in the small heterodimer partner gene promoter called sft4 and unlike ERRα and -β, it fails to activate a palindromic thyroid hormone response element. To investigate the mechanism behind this response element-specific differential transcriptional activity of ERRγ, the interactions of ERRγ and the aforementioned response elements was monitored. EMSA and chromatin immunoprecipitation assays demonstrated that ERRγ binds to sft4, SF-1RE, and palindromic thyroid hormone response element albeit with different degrees of affinity, but causes hyperacetylation of sft4 and SF-1RE templates only. Limited proteolysis assays showed that ERRγ, bound to different elements, shows differential trypsin sensitivity. A search for novel coregulators of ERRγ led to the identification of receptor interacting protein 140 as a potent corepressor and peroxisome proliferator-activated receptor γ coactivator 1 as a potent coactivator of ERRγ. DNA-dependent pull-down and transient transfection assays demonstrated that, on different DNA elements, ERRγ exhibits differential cofactor interactions, which in turn dictate its transcriptional activity. Because ERRγ shows a similar tissue distribution as peroxisome proliferator-activated receptor γ coactivator 1 and receptor interacting protein 140, these two coregulators may act as key components of ERRγ-mediated transcription.