Interplay between estrogen-related receptor alpha (ERRα) and gamma (ERRγ) on the regulation of ERRα gene expression

Estrogen-related receptor alpha (ERR alpha) modulates estrogen receptor (ER)-mediated activity and is participating in the energy homeostasis by regulation of downstream target genes. The ERR alpha gene itself is proposed to be regulated by peroxisome proliferator-activated receptory gamma coactivator (PGC-1 alpha) through an autoregulatory loop under physiological stimulation. We have previously shown that the close family member ERR gamma is a positive regulator of ERR alpha gene expression. ERRa and ERR gamma are coexpressed in metabolically active tissues such as heart, kidney and muscle, yet the physiological role of ERR gamma and its relationship with ERR alpha in gene regulation are currently unknown. The present study examined the interplay of ERR gamma and ERR alpha in regulation of ERR alpha gene expression. Using real-time PCR analyses we found that ERR gamma, like the ERR alpha and PGC-1a is induced in mouse liver during fasting. Overexpression of ERR gamma in the HEC-1B cells robustly stimulated the multi-hormone response element (MHRE) of the ERR alpha gene promoter and this activity was repressed by increasing expression of ERR alpha. The two ERRs bind MHRE simultaneously in electrophoretic mobility shift assay (EMSA) and they were detected as multimeric complexes in cells by commumoprecipitation. Although ERR alpha and ERR gamma share high sequence identity, they differ in biochemical and molecular characteristics as examined by trypsin digestion, reporter activation and coactivator interaction and utilization. Using chromatin immunoprecipitation (ChIP) assay, we showed that ectopic expression of both ERR alpha and ERR gamma modifies chromatin structure at the MHRE region while ectopic expression of PGC-1 alpha in HEC-1B cells promotes ERR gamma but not ERR alpha occupancy at the MHRE region of the ERRa gene promoter and enhances the recruitment of coactivator SRC1. These data suggested that ERR alpha and ERR gamma regulate ERR alpha gene expression with different molecular mechanisms. (c) 2006 Elsevier Ireland Ltd. All rights reserved.