Glucocorticoid-induction of hypothalamic aromatase via its brain-specific promoter

• Published in: Molecular and cellular endocrinology 2012-10, Vol.362 (1-2), p.85-90
• Main Authors: Brooks, D.C., Zhao, H., Yilmaz, M.B., Coon V, J.S., Bulun, S.E.
• Format: Article
• Language: English
• Subjects: Animals; antagonists; Aromatase; Aromatase - genetics; Aromatase - metabolism; biosynthesis; Cell Line; chromatin; Cy191a; dexamethasone; Dexamethasone - pharmacology; Enzyme Induction; Estradiol; Gene Knockdown Techniques; genes; Genes, Reporter; glucocorticoid receptors; Glucocorticoids; Glucocorticoids - pharmacology; Glucocorticoids - physiology; Hypothalamus; Hypothalamus - enzymology; Luciferases, Renilla - biosynthesis; Luciferases, Renilla - genetics; menstrual cycle; messenger RNA; Mice; mutants; Organ Specificity; Promoter Regions, Genetic; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; RNA Interference; secretion; sexual behavior; small interfering RNA; Transcriptional Activation; Up-Regulation
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2012.05.012

► We demonstrate glucocorticoid induction of Cyp19a1 via its brain-specific promoter. ► Inhibition of GR via siRNA or RU-486 ablates aromatase stimulation. ► Dexamethasone induces Cyp19a1 via a specific promoter region as shown by luciferase. ► GR recruitment to aromatase promoter I.f is demonstrated by ChIP. ► This mechanism might explain in part hypothalamic anovulation. In the brain, a 36-kb distal promoter (I.f) regulates the Cyp19a1 gene that encodes aromatase, the key enzyme for estrogen biosynthesis. Local estrogen production in the brain regulates critical functions such as gonadotropin secretion and sexual behavior. The mechanisms that control brain aromatase production are not well understood. Here we show that the glucocorticoid dexamethasone robustly increases aromatase mRNA and protein by up to 98-fold in mouse hypothalamic cell lines in a dose- and time-dependent fashion. Using deletion mutants of the brain-specific promoter I.f and chromatin immunoprecipitation-PCR, we isolated a distinct region (−500/−200bp) which becomes enriched in bound glucocorticoid receptor upon dexamethasone stimulation. A glucocorticoid antagonist or siRNA based knockdown of glucocorticoid receptor ablated dexamethasone stimulation of aromatase expression. Our findings demonstrate how glucocorticoids alter aromatase expression in the hypothalamus and might indicate a mechanism whereby glucocorticoid action modifies gonadotropin pulses and the menstrual cycle.