DNA-methylation/demethylation Networks in Brain of Alcoholic Subjects

新出现的证据表明，基因组的表观遗传失调，包括大脑区域特有的 DNA启动子甲基化改变与酒精滥用的神经病理表现有关 和依赖。DNA(胞嘧啶)甲基化通常被认为是一种高度稳定的表观遗传学 确保和保持神经元表型一致性的标记。然而，表观DNA标记是高度 动态的，需要一系列DNA甲基转移酶(DNMT)的作用和活跃的DNA去甲基化 碱基切除修复途径(BER途径)，包括5甲基胞嘧啶(5MC) 10-11易位(Tet)的羟基化和载脂蛋白B的脱氨 酶(APOBEC)。我们对双相(BP)障碍和重度抑郁症(MD)患者的初步研究 慢性酗酒者也表现出DNMT减少和Tet-1表达显著增加 前额叶皮质与对照组比较。在BP和MD合并酒精中毒的患者中，也有 GAD67和BDNF启动子上5-羟甲基纤维素含量增加。 本研究的目的是研究DNA甲基化部分的表达和启动子结合 慢性“单纯酗酒者”皮质边缘结构中的DNA去甲基化网络 (没有发育障碍，没有其他精神和神经障碍) 每天80克乙醇，从新南威尔士州组织资源中心获得(见附信)。 我们的工作假设是DNA甲基化/去甲基化动力学可能涉及行为 酒精暴露的某些方面部分是通过表观遗传学调节的 皮质边缘环路神经元的谷氨酸/氨基丁酸能传递和突触可塑性。 在一组不复杂的慢性酒精中毒受试者中测试这一假说将揭示新的酒精。 具有明显重要治疗和公共卫生影响的敏感靶点，蛋白质网络在 人脑具有明显的治疗和公共健康意义。

Emerging evidence suggests that an epigenetic misregulation of the genome, including brain region-specific altered DNA promoter methylation, is associated with the neuropathological manifestations of alcohol abuse and dependence. DNA (cytosine) methylation generally has been regarded as a highly stable epigenetic mark that ensures and maintains neuronal phenotype identity. However, the epigentic DNA marking is highly dynamic and requires the action of a family of DNA-methyltransferases (DNMT) and an active DNA-demethylation pathway (base excision repair [BER] pathway) that includes 5methyl cytosine (5MC) hydroxylation by a ten-eleven-translocation (TET) and deamination by an apolipoprotein B mRNA editing enzyme (Apobec). Our preliminary studies in bipolar (BP) disorder and major depressed (MD) patients who are also chronic alcoholics show decreased DNMT and a marked increase of TET-1 expression in the prefrontal cortex compared to controls. In BP and MD patients with comorbid alcoholism, there is also increased 5-hydroxyMC at GAD67 and BDNF promoters. The objective of our study is to investigate the expression and promoter binding of components of the DNA-methylation and DNA-demethylation network in corticolimbic structures of chronic "uncomplicated alcoholics" (no developmental disorders, no other psychiatric and neurological disorders) who consumed greater than 80 g of ethanol/day, obtained from the New South Wales Tissue Resource Center (see attached letter). Our working hypothesis is that DNA-methylation/demethylation dynamics may be involved in behavioral aspects of alcohol exposure in part through epigenetically mediated disruption of the balance between glutamatergic /GABAergic transmission and synaptic plasticity at corticolimbic circuit neurons. Testing this hypothesis in a cohort of "uncomplicated" chronic alcoholic subjects will reveal novel alcohol sensitive targets with obvious important therapeutic and public health implications, protein networks in human brain has obvious therapeutic and public health implications.