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

Abstract

Estrogen-related receptor α (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 multihormone 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.

Expression of estrogen, estrogen related and androgen receptors in adrenal cortex of intact adult male and female rats

“…Furthermore, it has been suggested that ERRg activates the DAX-1 promoter, which in turn inhibits ERRg through coactivator competition (an autoregulatory loop). Moreover, it was demonstrated that ERRg stimulates ERRa gene expression whereas its own gene product represses ERRg's activity [41].…”

Orphan Nuclear Receptor Estrogen-Related Receptor γ (ERRγ) Is Key Regulator of Hepatic Gluconeogenesis

“…However, ERR␣ did not affect the FSK-stimulated DNA binding ability of ERR␥ on Pck1 ERREs. Similarly, it has been shown that ERR␣ can inhibit ERR␥ transcriptional activity without affecting the DNA binding ability of ERR␥ and suggested that a mechanism for ERR␣ repression is the heterodimerization between the ERRs as evidenced by the reports showing that heterodimerization between ERR␣ and ERR␥ inhibits transactivation of each other, whereas homodimerization is needed for their transcriptional activity (32,48,49). On the other hand, their functions in terms of transcriptional regulation of each ERR for downstream targets are more complicated.…”

“…under Fasting-It has been reported that hepatic expression of ERR␥ rhythmically oscillates in the daily light/dark cycle and is induced during fasting (21,32), suggesting that it could be regulated by nutritional status. Because glucagon stimulates hepatic glucose production mainly through the cAMP signaling pathway under fasting (33), we first investigated whether ERR␥ expression is induced by the adenylate cyclase activator forskolin (FSK) in AML12 cells and rat primary hepatocytes.…”

Estrogen Induces Estrogen-related Receptor α Gene Expression and Chromatin Structural Changes in Estrogen Receptor (ER)-positive and ER-negative Breast Cancer Cells

“…ERR␣ and ERR␥ are known MHRE-binding proteins (63,66) and therefore candidate components of the MHRE binding complex detected in MCF-7 NPEs. The ER␣ could potentially be tethered to the MHRE and co-occupy the region with DNAbound ERRs (29) or, alternatively, may be tethered to AP1 (67)(68)(69) or SP1 (7,70) complexes bound to their consensus binding sites located upstream as well as within the MHRE nucleosome.…”