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，包括大脑区域特异性 DNA启动子甲基化改变与酒精滥用的神经病理学表现有关 和依赖。DNA（胞嘧啶）甲基化通常被认为是高度稳定的表观遗传 确保和维持神经元表型同一性的标记。然而，表观遗传DNA标记是高度 动态的，需要一个DNA甲基转移酶（DNMT）家族和一个活跃的DNA去甲基化酶的作用。 包括5甲基胞嘧啶（5 MC）的途径（碱基切除修复[BER]途径） 10 - 11易位（泰特）羟基化和载脂蛋白B mRNA编辑脱氨基 酶（Apobec）。我们在双相（BP）障碍和抑郁症（MD）患者中的初步研究， 慢性酒精中毒者也表现出DNMT降低和泰特-1表达的显著增加。 与对照组相比。在伴有酒精中毒的BP和MD患者中， 增加GAD 67和BDNF启动子处的5-羟MC。 本研究的目的是研究DNA甲基化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 (no发育障碍，无其他精神和神经系统疾病）， 80 g乙醇/天，从新南威尔士组织资源中心获得（见随附信函）。 我们的工作假设是，DNA甲基化/去甲基化动态可能涉及行为， 酒精暴露的各个方面，部分是通过表观遗传介导的平衡破坏， 皮质边缘回路神经元的谷氨酸能/GABA能传递和突触可塑性。 在一组“简单”的慢性酒精中毒受试者中测试这一假设， 具有明显重要治疗和公共卫生意义的敏感靶点， 人脑具有明显治疗和公共卫生意义。

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.