Alternative titles; symbols
HGNC Approved Gene Symbol: ESRRA
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:64,305,524-64,316,743 (from NCBI)
The estrogen-related receptors, ERR-alpha (ESRRA) and ERR-beta (ESRRB; 602167), form a subgroup of the steroid/thyroid/retinoid receptor family. They are homologous to the estrogen receptor (see 133430) and bind similar DNA targets; however, they are unable to activate gene transcription in response to estrogens (Sladek et al., 1997).
The orphan nuclear receptor estrogen-related receptor-alpha (ERRA), also called estrogen receptor-like 1 (ESRL1), was initially cloned by low-stringency screening of a human kidney cDNA library with an estrogen-receptor (133430) DNA binding domain probe (Giguere et al., 1988); however, it is not activated by classic estrogens. To identify possible physiologic functions for this orphan receptor, Sladek et al. (1997) cloned the mouse Err-alpha cDNA and used it to characterize the expression of Err-alpha transcripts and to identify potential target genes. RNA in situ hybridization studies detected Err-alpha transcripts in an organ-specific manner through mid- to late embryonic development. The gene was most highly expressed in kidney, heart, and brown adipocytes, all tissues that preferentially metabolize fatty acids. The ERR-alpha promoter region lacks the typical TATA and CAAT boxes but is GC rich and contains 10 consensus SP1 (189906)-binding elements and 2 E boxes. Binding site selection experiments showed preferential binding to an ERR-alpha response element (ERRE) containing a single consensus half-site, TNAAGGTCA.
Shi et al. (1997) found ESRRA transcripts with various transcription initiation start sites in human heart and placenta RNA and in human uterine cell lines. Northern blot analysis detected high expression of an approximately 2.4-kb transcript in heart and skeletal muscle, moderate expression in kidney, pancreas, small intestine, and colon, and low expression in all other tissues examined.
An ERRE is present in the 5-prime-flanking region of the gene encoding medium-chain acyl coenzyme A dehydrogenase (MCAD; 607008), a key enzyme involved in the mitochondrial beta-oxidation of fat. The MCAD nuclear receptor response element 1 (NRRE-1) interacts in vitro with ERR-alpha expressed in COS-7 cells. The results of Sladek et al. (1997) demonstrated that estrogen-related receptor-alpha can control the expression of MCAD through the NRRE-1 and thus may play an important role in regulating cellular energy balance in vivo.
Shi et al. (1997) determined that the ESRRA gene contains 7 exons and spans about 20 kb.
By interspecific backcross analysis, Sladek et al. (1997) mapped the Esrra locus mouse chromosome 19 and the Esrrb locus to mouse chromosome 12. Using fluorescence in situ hybridization, they mapped the human ESRRA gene to 11q12-q13 and the human ESRRB gene to 14q24.3. They mapped a processed ERR-alpha pseudogene to 13q12.1. To their knowledge, this was the first report of a pseudogene associated with a member of the nuclear receptor superfamily.
Luo et al. (2003) found that Esrra-null mice were viable and fertile, and displayed no gross anatomic alterations, with the exception of reduced body weight and reduced peripheral fat deposits. No significant changes in food consumption, energy expenditure, or serum biochemistry were observed in the mutant animals. However, mutants were resistant to high-fat diet-induced obesity. DNA microarray analysis of adipose tissue demonstrated mutant animals had altered regulation of enzymes involved in adipogenesis, energy metabolism, and lipid, eicosanoid, and steroid synthesis. Luo et al. (2003) concluded that ESRRA functions as a metabolic regulator.
Giguere, V., Yang, N., Segui, P., Evans, R. M. Identification of a new class of steroid hormone receptors. Nature 331: 91-94, 1988. [PubMed: 3267207] [Full Text: https://doi.org/10.1038/331091a0]
Luo, J., Sladek, R., Carrier, J., Bader, J.-A., Richard, D., Giguere, V. Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor-alpha. Molec. Cell Biol. 23: 7947-7956, 2003. [PubMed: 14585956] [Full Text: https://doi.org/10.1128/MCB.23.22.7947-7956.2003]
Shi, H., Shigeta, H., Yang, N., Fu, K., O'Brian, G., Teng, C. T. Human estrogen receptor-like (ESRL1) gene: genomic organization, chromosomal localization, and promoter characterization. Genomics 44: 52-60, 1997. [PubMed: 9286700] [Full Text: https://doi.org/10.1006/geno.1997.4850]
Sladek, R., Bader, J.-A., Giguere, V. The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Molec. Cell. Biol. 17: 5400-5409, 1997. [PubMed: 9271417] [Full Text: https://doi.org/10.1128/MCB.17.9.5400]
Sladek, R., Beatty, B., Squire, J., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Giguere, V. Chromosomal mapping of the human and murine orphan receptors ERR-alpha (ESRRA) and ERR-beta (ESRRB) and identification of a novel human ERR-alpha-related pseudogene. Genomics 45: 320-326, 1997. [PubMed: 9344655] [Full Text: https://doi.org/10.1006/geno.1997.4939]