title: Histone modifications of the Crhr1 gene in a rat model of depression following chronic stress.
abstract: Multiple lines of evidence suggest a link between depression and changes in hypothalamic-pituitary-adrenal (HPA)-axis hormone dynamics, including altered regulation of the corticotrophin-releasing hormone (CRH) and its main receptor, corticotrophin-releasing hormone receptor 1 (CRHR1). However, the precise molecular mechanisms underlying depression remain poorly understood. In this study, we employed a model of depression in rats by subjecting animals to 21 days of chronic unpredictable mild stress (CUMS). Real-time PCR and western blotting were used to study the mRNA and protein expression levels of CRHR1 in the hypothalamus. In addition, chromatin immunoprecipitation assays were used to detect histone methylation at the Crhr1 gene promoter; the levels of histone H3 trimethylation at lysines 4 (H3K4) and 9 (H3K9) reflect active transcription and transcriptional repression, respectively. Rats exposed to CUMS exhibited significant reduction in locomotion and sucrose preference. These behavioral alterations were associated with elevated expression levels of CRHR1 mRNA and protein in the hypothalamus of rats in the CUMS group. We also found that the levels of H3K9 trimethylation at the Crhr1 gene promoter in the CUMS group were significantly lower than those in the control group, whereas H3K4 trimethylation levels were the same for both groups. Taken together, our findings suggest that the increase in CRHR1 expression in the hypothalamus of stressed rats correlates with a decrease in the repressive chromatin state caused by reduced H3K9 trimethylation levels. These data are the first in vivo evidence of a role for chromatin modifications in the regulation of Crhr1 gene expression in the hypothalamus, and may provide novel insight into therapeutic approaches to treat depression.
authors.affiliation: Department of Psychiatry, Renmin Hospital, Wuhan University, Jiefang Road 238#, Wuhan 430060, PR China.
authors.forename: Qirong
authors.initials: Q
authors.lastname: Wan
authors.affiliation: Department of Psychiatry, Renmin Hospital, Wuhan University, Jiefang Road 238#, Wuhan 430060, PR China.
authors.forename: Kai
authors.initials: K
authors.lastname: Gao
authors.affiliation: Department of Psychiatry, Renmin Hospital, Wuhan University, Jiefang Road 238#, Wuhan 430060, PR China.
authors.forename: Han
authors.initials: H
authors.lastname: Rong
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Psychiatry, Renmin Hospital, Wuhan University, Jiefang Road 238#, Wuhan 430060, PR China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Renmin Hospital, Wuhan University, Jiefang Road 238#, Wuhan 430060, PR China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Renmin Hospital, Wuhan University, Jiefang Road 238#, Wuhan 430060, PR China; Institute of Neuropsychiatry, Wuhan University, Wuhan 430060, PR China. Electronic address: wanggaohuad@tom.com.
authors.forename: Gaohua
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Renmin Hospital, Wuhan University, Jiefang Road 238#, Wuhan 430060, PR China; Institute of Neuropsychiatry, Wuhan University, Wuhan 430060, PR China. Electronic address: zcliu6@whu.edu.cn.
authors.forename: Zhongchun
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002908:Chronic Disease; D003863:Depression / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D004195:Disease Models, Animal; D006657:Histones / Q000235:genetics*; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D008745:Methylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications*; D000099052:CRF Receptor, Type 1
chemical_list: D006657:Histones; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
keywords: CRHR1; Depression; Epigenetic regulation; Histone methylation; Hypothalamus