Deoxyribonucleic acid response element-dependent regulation of transcription by orphan nuclear receptor estrogen receptor-related receptor γ

The estrogen receptor-related receptor gamma (ERRgamma/ ERR3/NR3B3) is the newest member of the ERR subfamily that also includes ERRalpha and ERRbeta. All three isoforms share a high degree of amino acid identity especially in the DNA binding domain. ERRgamma 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 ERRalpha and -beta, it fails to activate a palindromic thyroid hormone response element. To investigate the mechanism behind this response element-specific differential transcriptional activity of ERRgamma, the interactions of ERRgamma and the aforementioned response elements was monitored. EMSA and chromatin immunoprecipitation assays demonstrated that ERRgamma 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 ERRgamma, bound to different elements, shows differential trypsin sensitivity. A search for novel coregulators of ERRgamma led to the identification of receptor interacting protein 140 as a potent corepressor and peroxisome proliferator-activated receptor gamma coactivator 1 as a potent coactivator of ERRgamma. DNA-dependent pull-down and transient transfection assays demonstrated that, on different DNA elements, ERRgamma exhibits differential cofactor interactions, which in turn dictate its transcriptional activity. Because ERRgamma shows a similar tissue distribution as peroxisome proliferator-activated receptor gamma coactivator 1 and receptor interacting protein 140, these two coregulators may act as key components of ERRgamma-mediated transcription.