Estrogen stimulates estrogen-related receptor alpha gene expression through conserved hormone response elements

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Estrogen-related receptor alpha (ERR alpha) is a nuclear receptor structurally similar to estrogen receptors (ERs).
• ERR alpha influences ER-mediated signaling pathways and is expressed in various tissues.
• Previous work indicated estrogen stimulates ERR alpha gene expression in the mouse uterus.

Purpose of the Study:

• To investigate the regulation of the ERR alpha gene by estrogen in different tissues and cell lines.
• To identify the molecular mechanisms underlying estrogen-induced ERR alpha gene expression.
• To confirm ERR alpha as a downstream target of ER alpha.

Main Methods:

• Gene expression analysis in mouse tissues (uterus, heart, liver) and human cell lines (breast, endometrial).
• Analysis of the human ERR alpha gene promoter, including Sp1 binding sites and a 34-bp DNA element with multiple steroid hormone response element half-sites (MHREs).
• Transient transfection experiments, site-directed mutagenesis, and chromatin immunoprecipitation assays in MCF-7 cells.

Main Results:

• Estrogen stimulates ERR alpha gene expression in the mouse uterus and heart, but not in the liver.
• Estrogen also upregulates ERR alpha expression in human breast and endometrial cell lines.
• The Sp1 protein is essential for ERR alpha promoter activity, and a conserved MHRE element mediates the estrogen response.
• ER alpha directly binds to the endogenous ERR alpha gene promoter in vivo, with binding enhanced by estrogen treatment.

Conclusions:

• The ERR alpha gene is a direct downstream target of estrogen receptor alpha (ER alpha).
• Estrogen-mediated regulation of ERR alpha involves specific DNA elements (MHREs) and transcription factors like Sp1.
• These findings elucidate a novel regulatory pathway in estrogen signaling with implications for tissues like the uterus and breast.