A polymorphic autoregulatory hormone response element in the human estrogen-related receptor alpha (ERRalpha) promoter dictates peroxisome proliferator-activated receptor gamma coactivator-1alpha control of ERRalpha expression

• Published in: The Journal of biological chemistry 2004-04, Vol.279 (18), p.18504-18510
• Main Authors: Laganière, Josée, Tremblay, Gilles B, Dufour, Catherine R, Giroux, Sylvie, Rousseau, François, Giguère, Vincent
• Format: Article
• Language: English
• Subjects: Canada - epidemiology; DNA Mutational Analysis; ERRalpha Estrogen-Related Receptor; Feedback, Physiological - genetics; Female; Gene Dosage; Genetic Testing; Heat-Shock Proteins - physiology; Hormones - physiology; Humans; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Polymorphism, Genetic; Promoter Regions, Genetic - genetics; Receptors, Cytoplasmic and Nuclear - biosynthesis; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Estrogen - biosynthesis; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Response Elements - genetics; Transcription Factors - metabolism; Transcription Factors - physiology
• ISSN: 0021-9258

The orphan nuclear estrogen-related receptor alpha (ERRalpha) and transcriptional cofactor peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) are involved in the regulation of energy metabolism. Recently, extensive cross-talk between PGC-1alpha and ERRalpha has been demonstrated. The presence of PGC-1alpha is associated with an elevated expression of ERRalpha, and the two proteins can influence the transcriptional activities of one another. Using a candidate gene approach to detect regulatory variants within genes encoding nuclear receptors, we have identified a 23-bp sequence (ESRRA23) containing two nuclear receptor recognition half-site motifs that is present in 1-4 copies within the promoter of the human ESRRA gene encoding ERRalpha. The ESRRA23 sequence contains a functional ERR response element that is specifically bound by ERRalpha, and chromatin immunoprecipitation shows that endogenous ERRalpha occupies its own promoter in vivo. Strikingly, introduction of PGC-1alpha in HeLa cells by transient transfection induces the activity of the ESRRA promoter in a manner that is dependent on the presence of the ESRRA23 element and on its dosage. Coexpression of ERRalpha and PGC-1alpha results in a synergistic activation of the ESRRA promoter. In experiments using ERRalpha null fibroblasts, the ability of PGC-1alpha to stimulate the ESRRA promoter is considerably reduced but can be restored by addition of ERRalpha. Taken together, these results demonstrate that an interdependent ERRalpha/PGC-1alpha-based transcriptional pathway targets the ESRRA23 element to dictate the level of ERRalpha expression. This study further suggests that this regulatory polymorphism may provide differential responses to ERRalpha/PGC-1alpha-mediated metabolic cues in the human population.