DNA methylation in the medial prefrontal cortex regulates alcohol-related behavior in rats
Received date: 2019-09-02
Revised date: 2019-11-21
Online published: 2019-12-25
Supported by
Supported by the National Natural Science Foundation of China No(81373247);the Innovative Project for College Students of Zhengzhou University No(2019cxcy054)
Alcohol abuse causes tissue and organ damage, and may participate neuropsychiatric diseases. Studies have shown that DNA methylation plays an important role in gene expression and behavioral changes induced by alcohol, however the causative neurobiological mechanisms have not been clarified. In this study, 32 healthy adult male SD rats were randomly divided into a drinking water control group (n=16) and a chronic alcohol exposure group (n=16). The alcohol preference and locomotor activity of rats were evaluated by two-bottle choice test (TBCT) and open-field test (OFT). DNA methylation in the medial prefrontal cortex (mPFC) tissue was detected by the reduced representative bisulfite sequencing (RRBS) technology. The methylation differential genes closely related to alcohol abuse were screened. qRT-PCR was used to verify the mRNA expression patterns of differential genes. qRT-PCR and Western blot were used to detect the expression of DNA methyltransferases (DNMTs) and methyl CpG binding protein 2 (MeCP2). Furthermore, the effect of short-term alcohol exposure (7 days) on DNMTs and MeCP2 in the mPFC of rats was tested (n=8/group). The results indicated that the methylation level of promoter region in the mPFC of rats exposed to chronic alcohol was significantly increased. In addition, the increased methylation levels in the promoter of Ntf3 and Ppm1G were accompanied by down-regulated mRNA levels in the chronic alcohol exposure group. The decreased methylation levels in the promoter of Hap1 and DUSP1 were accompanied by up-regulated mRNA levels. Furthermore, chronic alcohol exposure increased the mRNA and protein levels of DNMT3B and MeCP2. However, short term alcohol exposure did not affect their expression. This present study provides evidence that DNA methylation is associated with the development of alcohol abuse, which may be regulated by DNMT3B and MeCP2. The target genes Ntf3, Ppm1G, Hap1, and DUSP1 related to alcohol abuse were discovered as well, providing new insights into the neurobiological mechanism of alcohol abuse and the potential pharmacological targets for the treatment of alcohol abuse.
Hengzhen Cui, Mizhu Sun, Runzhi Wang, Chenyu Li, Yuxuan Huang, Qiuju Huang, Xiaomeng Qiao . DNA methylation in the medial prefrontal cortex regulates alcohol-related behavior in rats[J]. Hereditas(Beijing), 2020 , 42(1) : 112 -125 . DOI: 10.16288/j.yczz.19-261
| [1] | Peacock A, Leung J, Larney S, Colledge S, Hickman M, Rehm J, Giovino GA, West R, Hall W, Griffiths P, Ali R, Gowing L, Marsden J, Ferrari AJ, Grebely J, Farrell M, Degenhardt L . Global statistics on alcohol, tobacco and illicit drug use: 2017 status report. Addiction, 2018,113(10):1905-1926. |
| [2] | WHO. Global status report on alcohol and health. World Health Organization, 2014. |
| [3] | Lu SJ, Du SM, Hu XQ, Zou SR, Liu WJ, Ba L, Ma GS . Drinking patterns and the association between socio- demographic factors and adolescents' alcohol use in three metropolises in China. Int J Environ Res Public Health, 2015,12(2):2037-2053. |
| [4] | Antonelli M, Ferrulli A, Sestito L, Vassallo GA, Tarli C, Mosoni C, Rando MM, Mirijello A, Gasbarrini A, Addolorato G . Alcohol addiction-the safety of available approved treatment options. Expert Opin Drug Saf, 2018,17(2):169-177. |
| [5] | Yang X, Zhang H, Lai J . Alcohol dependence mediated by monoamine neurotransmitters in the central nervous system. Hereditas (Beijing), 2014,36(1):11-20. |
| [5] | 杨晓华, 张华峰, 赖江华 . 中枢单胺类神经递质在酒精依赖中的分子作用机制. 遗传, 2014,36(1):11-20. |
| [6] | He GF, Zhong SR, Jing Q . Genetic polymorphism for genes of alcohol dependence. Hereditas (Beijing), 2008,30(4):413-418. |
| [6] | 贺艮峰, 钟树荣, 景强 . 酒精依赖相关基因的遗传多态性. 遗传, 2008,30(4):413-418. |
| [7] | Nestler EJ . Epigenetic mechanisms of drug addiction. Neuropharmacology, 2014,76:259-268. |
| [8] | Zhu ZZ, Hou LF, Bollati V, Tarantini L, Marinelli B, Cantone L, Yang AS, Vokonas P, Lissowska J, Fustinoni S, Pesatori AC, Bonzini M, Apostoli P, Costa G, Bertazzi PA, Chow WH, Schwartz J, Baccarelli A . Predictors of global methylation levels in blood DNA of healthy subjects: a combined analysis. Int J Epidemiol, 2012,41(1):126-139. |
| [9] | Ruggeri B, Nymberg C, Vuoksimaa E, Lourdusamy A, Wong CP, Carvalho FM, Jia T, Cattrell A, Macare C, Banaschewski T, Barker GJ, Bokde AL, Bromberg U, Büchel C, Conrod PJ, Fauth-Bühler M, Flor H, Frouin V, Gallinat J, Garavan H, Gowland P, Heinz A, Ittermann B, Martinot JL, Nees F, Pausova Z, Paus T, Rietschel M, Robbins T, Smolka MN, Spanagel R, Bakalkin G, Mill J, Sommer WH, Rose RJ, Yan J, Aliev F, Dick D, Kaprio J, Desrivières S, Schumann G . Association of protein phosphatase PPM1G with alcohol use disorder and brain activity during behavioral control in a genome-wide methylation analysis. Am J Psychiatry, 2015,172(6):543-552. |
| [10] | Barker JM, Zhang YQ, Wang F, Taylor JR, Zhang HP . Ethanol-induced Htr3a promoter methylation changes in mouse blood and brain. Alcohol Clin Exp Res, 2013,37(s1):E101-E107. |
| [11] | Barbier E, Tapocik JD, Juergens N, Pitcairn C, Borich A, Schank JR, Sun H, Schuebel K, Zhou Z, Yuan Q, Vendruscolo LF, Goldman D, Heilig M . DNA methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity. . Neurosci, 2015,35(15):6153-6164. |
| [12] | Qiao XM, Yin FY, Ji YY, Li YX, Yan P, Lai JH . 5-Aza-2'-deoxycytidine in the medial prefrontal cortex regulates alcohol-related behavior and Ntf3-TrkC expression in rats. PLoS One, 2017,12(6):e0179469. |
| [13] | Boerngen-Lacerda R, Souza-Formigoni ML . Does the increase in locomotion induced by ethanol indicate its stimulant or anxiolytic properties? Pharmacol Biochem Behav, 2000,67(2):225-232. |
| [14] | Boschen KE, Hamilton GF, Delorme JE, Klintsova AY . Activity and social behavior in a complex environment in rats neonatally exposed to alcohol. Alcohol 2014; 48:533-541. |
| [15] | Buckner JD, Terlecki MA . Social anxiety and alcohol- related impairment: The mediational impact of solitary drinking. Addict Behav, 2016,58:7-11. |
| [16] | Colombo G, Lobina C, Lorrai I, Acciaro C, Maccioni P, Gessa GL . Binge drinking and anxiety at the end of the nocturnal period in alcohol-preferring sP rats. Alcohol, 2017,63:27-32. |
| [17] | Thorberg FA, Young RM, Hasking P, Lyvers M, Connor JP, London ED, Huang YL, Feeney GFX . Alexithymia and alcohol dependence: The roles of negative mood and alcohol craving. Subst Use Misuse, 2019,54(14):1-7. |
| [18] | Charlet K, Heinz A . Harm reduction-a systematic review on effects of alcohol reduction on physical and mental symptoms. Addict Biol, 2017,22(5):1119-1159. |
| [19] | B?nsch D, Lenz B, Fiszer R, Frieling H, Kornhuber J, Bleich S . Lowered DNA methyltransferase (DNMT-3b) mRNA expression is associated with genomic DNA hypermethylation in patients with chronic alcoholism. . Neural Transm (Vienna), 2006,113(9):1299-1304. |
| [20] | B?nsch D, Lenz B, Reulbach U, Kornhuber J, Bleich S . Homocysteine associated genomic DNA hypermethylation in patients with chronic alcoholism. . Neural Transm (Vienna), 2004,111(12):1611-1616. |
| [21] | Weng JT, Wu LS, Lee CS, Hsu PW, Cheng AT . Integrative epigenetic profiling analysis identifies DNA methylation changes associated with chronic alcohol consumption. Comput Biol Med, 2015,64:299-306. |
| [22] | Usui N, Watanabe K, Ono K, Tomita K, Tamamaki N, Ikenaka K, Takebayashi H . Role of motoneuron-derived neurotrophin 3 in survival and axonal projection of sensory neurons during neural circuit formation. Development, 2012,139(6):1125-1132. |
| [23] | Han KA, Woo D, Kim S, Choii G, Jeon S, Won SY, Kim HM, Heo WD, Um JW, Ko J . Neurotrophin-3 regulates synapse development by modulating trkc-ptpσ synaptic adhesion and intracellular signaling pathways. . Neurosci, 2016,36(17):4816-4831. |
| [24] | Tang TS, Tu HP, Chan EYW, Maximov A, Wang ZN, Wellington CL, Hayden MR, Bezprozvanny I . Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron, 2003,39(2):227-239. |
| [25] | Czeredys M, Vigont VA, Boeva VA, Mikoshiba K, Kaznacheyeva EV, Kuznicki J . Huntingtin-associated protein 1a regulates store-operated calcium entry in medium spiny neurons from transgenic YAC128 mice, a model of huntington's disease. Front Cell Neurosci, 2018,12:381. |
| [26] | Kim SH, Yu HS, Park HG, Park S, Seo MS, Jeon WJ, Ahn YM, Ha K, Shin SY, Kim YS . Role of MKP-1 (DUSP1) in clozapine-induced effects on the ERK1/2 signaling pathway in the rat frontal cortex. Psychopharmacology (Berl), 2013,230:425-437. |
| [27] | Turek-Plewa J, Jagodziński PP . The role of mammalian DNA methyltransferases in the regulation of gene expression. Cell Mol Biol Lett, 2005,10(4):631-647. |
| [28] | Dajun D . DNA methylation and demethylation: current status and future perspective. Hereditas (Beijing), 2014,36(5):403-410. |
| [28] | 邓大君 . DNA甲基化和去甲基化的研究现状及思考. 遗传, 2014,36(5):403-410. |
| [29] | Heyward FD, Sweatt JD . DNA methylation in memory formation: emerging insights. Neuroscientist, 2015,21(5):475-489. |
| [30] | Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, Silva AJ, Fan GP . Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci, 2010,13(4):423-430. |
| [31] | LaPlant Q, Vialou V, Covington HE, Dumitriu D, Feng J, Warren BL, Maze I, Dietz DM, Watts EL, I?iguez SD, Koo JW, Mouzon E, Renthal W, Hollis F, Wang H, Noonan MA, Ren Y, Eisch AJ, Bola?os CA, Kabbaj M, Xiao G, Neve RL, Hurd YL, Oosting RS, Fan G, Morrison JH, Nestler EJ . Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci, 2010,13(9):1137-1143. |
| [32] | Repunte-Canonigo V, Chen J, Lefebvre C, Kawamura T, Kreifeldt M, Basson O, Roberts AJ, Sanna PP . MeCP2 regulates ethanol sensitivity and intake. Addict Biol, 2014,19(5):791-799. |
| [33] | Zhang HP, Gelernter J . Review: DNA methylation and alcohol use disorders: Progress and challenges. Am J Addict, 2017,26(5):502-515. |
/
| 〈 |
|
〉 |
www.chinagene.cn
备案号：京ICP备09063187号
