Gestational choline supplementation normalized fetal alcohol-induced alterations in histone modifications, DNA methylation, and proopiomelanocortin (POMC) gene expression in β-endorphin-producing POMC neurons of the hypothalamus.
Gestational choline supplementation normalized fetal alcohol-induced alterations in histone modifications, DNA methylation, and proopiomelanocortin (POMC) gene expression in β-endorphin-producing POMC neurons of the hypothalamus.
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DOI：
10.1111/acer.12082
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Sarkar DK
中科院分区：
文献类型：
--
作者：
Bekdash RA;Zhang C;Sarkar DK
产前暴露于乙醇降低下丘脑前阿黑皮素（POMC）基因的表达，已知控制各种生理功能，包括机体的应激反应。在这项研究中，我们确定POMC神经元功能的变化是否与POMC产生神经元中组蛋白修饰酶和DNA甲基化酶的表达改变有关，因为已知这些酶参与基因表达的调节。此外，我们测试了妊娠期补充胆碱是否可以预防乙醇对这些神经元的不良影响。在妊娠第7天和第21天，用含酒精的流质饮食或对照饮食（含或不含胆碱）喂养妊娠大鼠母鼠，并在成年期使用其雄性后代大鼠。采用免疫组化、实时荧光定量RT-PCR和甲基化特异性RT-PCR方法，检测了成年雄性子代大鼠下丘脑组织蛋白修饰酶和DNA甲基化酶的蛋白和mRNA水平，以及POMC基因甲基化和表达的变化。此外，我们测量了基础和脂多糖（LPS）诱导的血浆皮质酮水平的酶联免疫吸附试验。产前乙醇处理抑制下丘脑组蛋白激活标记（H3 K4 me 3、Set 7/9、乙酰化H3 K9、磷酸化H3 S10）的蛋白和mRNA水平，增加抑制标记（H3 K9 me 2、G9 a、Setdb 1）、DNA甲基化酶（Dnmt 1）和甲基CpG结合蛋白（MeCP 2）。结果表明，LPS处理后POMC基因甲基化水平升高，POMC mRNA和β-EP水平降低，皮质酮对LPS的反应增强。胆碱使乙醇改变的蛋白质和H3 K4 me 3、Set 7/9、H3 K9 me 2、G9 a、Setdb 1、Dnmt 1和MeCP 2的mRNA水平正常化。它还使POMC基因甲基化和基因表达、β-EP产生和皮质酮对LPS的反应的变化正常化。这些数据表明，产前乙醇调节POMC神经元中的组蛋白和DNA甲基化，可能导致POMC基因的高甲基化和POMC基因表达的降低。妊娠期补充胆碱可以防止乙醇对这些神经元的不良影响。
Prenatal exposure to ethanol reduces the expression of hypothalamic proopiomelanocortin (POMC) gene, known to control various physiological functions including the organismal stress response. In this study, we determined whether the changes in POMC neuronal functions are associated with altered expressions of histone-modifying and DNA-methylating enzymes in POMC-producing neurons, since these enzymes are known to be involved in regulation of gene expression. In addition, we tested whether gestational choline supplementation prevents the adverse effects of ethanol on these neurons. Pregnant rat dams were fed with alcohol-containing liquid diet or control diet during gestational days 7 and 21 with or without choline, and their male offspring rats were used during the adult period. Using double-immunohistochemistry, real-time reverse transcription polymerase chain reaction (RT-PCR) and methylation specific RT-PCR, we determined protein and mRNA levels of histone-modifying and DNA-methylating enzymes, and the changes in POMC gene methylation and expression in the hypothalamus of adult male offspring rats. Additionally, we measured the basal and lipopolysaccharide (LPS)-induced corticosterone levels in plasma by enzyme-linked immunoabsorbent assay. Prenatal ethanol treatment suppressed hypothalamic levels of protein and mRNA of histone activation marks (H3K4me3, Set7/9, acetylated H3K9, phosphorylated H3S10) increased the repressive marks (H3K9me2, G9a, Setdb1) and DNA methylating enzyme (Dnmt1) and the methyl-CpG-binding protein (MeCP2). The treatment also elevated the level of POMC gene methylation, while it reduced levels of POMC mRNA and β-EP, and elevated corticosterone response to LPS. Gestational choline normalized the ethanol-altered protein and the mRNA levels of H3K4me3, Set7/9, H3K9me2, G9a, Setdb1, Dnmt1 and MeCP2. It also normalizes the changes in POMC gene methylation and gene expression, β-EP production and the corticosterone response to LPS. These data suggest that prenatal ethanol modulates histone and DNA methylation in POMC neurons that may be resulting in hypermethylation of POMC gene and reduction of POMC gene expression. Gestational choline supplementation prevents the adverse effects of ethanol on these neurons.
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影响因子：
8
作者：
Kim, J. K.;Samaranayake, M.;Pradhan, S.
通讯作者：
Pradhan, S.
影响因子：
4.8
作者：
Holler, T;Cermak, JM;Blusztajn, JK
通讯作者：
Blusztajn, JK
影响因子：
3.7
作者：
Liu Y;Balaraman Y;Wang G;Nephew KP;Zhou FC
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Zhou FC
影响因子：
10.6
作者：
Govorko, Dmitry;Bekdash, Rola A.;Zhang, Changqing;Sarkar, Dipak K.
通讯作者：
Sarkar, Dipak K.
DOI：
10.1111/j.1469-7610.2008.01909.x
发表时间：
2008-10-01
影响因子：
7.6
作者：
Mill, Jonathan;Petronis, Arturas
通讯作者：
Petronis, Arturas