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Gene Regulation Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA

(Requests for offprints should be addressed to C T Teng; Email: teng{at}niehs.nih.gov)

^* (D Liu and Z Zhang contributed equally to this work)

The expression of estrogen-related receptor- (ERR) is stimulated by estrogen in selective tissues. Recently, a correlation between ERR expression and the induction of peroxisome proliferator-activated receptor- coactivator-1 (PGC-1) in the liver of fasting animals and in cold-stressed brown-fat tissues and skeletal muscle was shown. To explore the molecular mechanisms of ERR regulation by diverse signals, the promoter of the human ERR gene was cloned and characterized. Mutation and deletion analyses revealed that a 53 bp region containing repeated core element AGGTCA motifs of the ERR 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, ERR bound to and robustly stimulated the transcription of reporters containing at least two AGGTCA motifs. Ectopic expression of PGC-1 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 ERR by small interfering RNA, and increasing the ERR level by ectopic expression, substantially decreased and increased respectively the transactivation capability of PGC-1. The activation function 2 domain of the ERR and the L2 and L3 motifs of PGC-1 were essential to transactivate the MHRE. Additionally, PGC-1 increases the amount of endogenous ERR bound to the MHRE region as determined by a chromatin immunoprecipitation assay. The present study demonstrates that the MHRE of the ERR gene is a target for ERR transactivation, which is enhanced by PGC-1.

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