Histone deacetylase 1 (HDAC1) participates in the down-regulation of corticotropin releasing hormone gene (crh) expression

PHYSIOLOGY & BEHAVIOR

卷:104

Article

Miller, Lydia^2,3,4  Foradori, Chad D.^5,6  Lalmansingh, Avin S.^2,3,4  Handa, Robert J.^5,6  Uht, Rosalie M.^1,2,3,4 

[1] Univ N Texas Hlth Sci Ctr Ft Worth, Inst Aging & Alzheimers Dis, Dept Pharmacol & Neurosci, Ft Worth, TX 76107 USA

[2] Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA

[3] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA

[4] Univ Virginia, Neurobiol Program, Charlottesville, VA 22908 USA

[5] Colorado State Univ, Dept Biomed Sci, Ft Collins, CO 80523 USA

[6] Univ Arizona, Coll Med Phoenix, Dept Basic Med Sci, Phoenix, AZ 85004 USA

关键词: Corticotropin releasing factor;    Gene expression;    Histone deacetylase 1;   

DOI  :  10.1016/j.physbeh.2011.03.026

来源: Elsevier

【 摘 要 】

The paraventricular nucleus of the hypothalamus (PVH) plays a central role in regulating the hypothalamicpituitary-adrenal (HPA) axis. Medial parvocellular neurons of the PVH (mpPVH) integrate sensory and humoral inputs to maintain homeostasis. Humoral inputs include glucocorticoids secreted by the adrenals, which down-regulate HPA activation. A primary glucocorticoid target is the population of mpPVH neurons that synthesize and secrete corticotropin-releasing factors, the most potent of which is corticotropin-releasing hormone (CRH). Although CRH gene (crh) expression is known to be down-regulated by glucocorticoids, the mechanisms by which this process occurs are still poorly understood. To begin this study we postulated that glucocorticoid repression of crh involves HDAC recruitment to the region of the crh proximal promoter. To evaluate this hypothesis, we treated hypothalamic cells that express CRH with the HDAC inhibitor trichostatin A (TSA). As predicted, treatment with TSA led to increased CRH mRNA levels and crh promoter activity. Although co-treatment with Dex (10(-7) M) reduced the TSA effect on mRNA levels, it failed to reduce promoter activity; however co-transfection of HDAC1 but not 3 restored Dex inhibition. A distinction between HDAC1 and 3 was also apparent with respect to crh promoter occupancy. Dex led to increased HDAC1 but not HDAC3 occupancy. In vivo studies revealed that CRH-immunoreactive (-ir) neurons contained HDAC1 - and HDAC3-ir. Collectively, these data point to a role for HDAC1 in the physiologic regulation of crh. (C) 2011 Elsevier Inc. All rights reserved.

【 授权许可】

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