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

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