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Estradiol Regulates Corticotropin-Releasing Hormone Gene (crh) Expression in a Rapid and Phasic Manner that Parallels Estrogen Receptor- and -β Recruitment to a 3',5'-Cyclic Adenosine 5'-Monophosphate Regulatory Region of the Proximal crh Promoter

Neuroscience Graduate Program (A.S.L., R.M.U.) and Departments of Pathology (R.M.U.) and Biochemistry and Molecular Genetics (R.M.U), University of Virginia School of Medicine, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Rosalie M. Uht, M.D., Ph.D., Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, P.O. Box 800733, Charlottesville, Virginia 22908-0733. E-mail: ruht{at}virginia.edu.

In the central nervous system, CRH regulates several affective states. Dysregulation of neuronal crh expression in the paraventricular nucleus of the hypothalamus correlates with some forms of depression, and amygdalar crh expression may modulate levels of anxiety. Because estrogens modulate these states, we sought to determine 17β-estradiol (E2) effects on crh expression. CRH mRNA levels were measured in the AR-5 amygdaloid cell line by RT-PCR analysis. They increased by 1 min of E2 treatment, suggesting that crh behaves as an immediate-early gene. After peaking at 3 min, CRH mRNA returned to basal levels and then increased by 60 min. To dissect some of the molecular mechanisms underlying these events, we measured occupancy of the crh promoter by estrogen receptors (ERs) and coactivators, using chromatin immunoprecipitation. Because this promoter does not contain palindromic estrogen response elements, we targeted the region of a cAMP regulatory element (CRE), implicated in crh regulation. The temporal pattern of the mRNA response was mimicked by recruitment of ER and -β, phospho-CRE-binding protein, coactivators steroid receptor coactivator-1 and CRE-binding protein-binding protein (CBP), and an increase in histone 3 and 4 acetylation. Lastly, ER and -β loading were temporally dissociated, peaking at 1 and 3 min, respectively. The ER peaks were associated with coactivators and acetylation patterns. ER associated with phospho-CRE-binding protein, CBP, steroid receptor coactivator-1, and increased acetylated histone 3. ERβ associated with CBP and increased acetylated histone 4. The tight temporal correlation between E2-induced CRH mRNA levels and promoter occupancy by ERs strongly suggest that E2 regulates crh expression through an ER- and/or ERβ-CRE alternate pathway.

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