Glucocorticoid-induction of hypothalamic aromatase via its brain-specific promoter.
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/-200 bp) 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.
Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Chicago, IL 60611, United States.
D C
DC
Brooks
H
H
Zhao
M B
MB
Yilmaz
J S
JS
Coon V
S E
SE
Bulun
D000818:Animals; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology*; D007031:Hypothalamus / Q000201:enzymology*; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D049410:Luciferases, Renilla; D001141:Aromatase