Estrogen-related receptor-γ and peroxisome proliferator-activated receptor-γ coactivator-1α regulate estrogen-related receptor-α gene expression via a conserved multi-hormone response element

Abstract

The expression of estrogen-related receptor-α (ERRα) is stimulated by estrogen in selective tissues. Recently, a correlation between ERRα expression and the induction of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in the liver of fasting animals and in cold-stressed brown-fat tissues and skeletal muscle was shown. To explore the molecular mechanisms of ERRα regulation by diverse signals, the promoter of the human ERRα gene was cloned and characterized. Mutation and deletion analyses revealed that a 53 bp region containing repeated core element AGGTCA motifs of the ERRα gene serves as a multi-hormone response element (MHRE) for several nuclear receptors in transient co-transfection studies of human endometrial carcinoma (HEC-1B) cells. Among the nuclear receptors tested, ERRγ bound to and robustly stimulated the transcription of reporters containing at least two AGGTCA motifs. Ectopic expression of PGC-1α in HEC-1B cells strongly activated the reporter containing the MHRE, presumably via the endogenous nuclear receptor binding to the element. Reducing the endogenous level of ERRγ by small interfering RNA, and increasing the ERRγ level by ectopic expression, substantially decreased and increased respectively the transactivation capability of PGC-1α. The activation function 2 domain of the ERRγ and the L2 and L3 motifs of PGC-1α were essential to transactivate the MHRE. Additionally, PGC-1α increases the amount of endogenous ERRγ bound to the MHRE region as determined by a chromatin immunoprecipitation assay. The present study demonstrates that the MHRE of the ERRα gene is a target for ERRγ transactivation, which is enhanced by PGC-1α.