Genetic and Epigenetic Regulation of Addiction Genes

药物成瘾是一种复杂的疾病，具有很强的遗传成分，而表观遗传因素的作用 仍然悬而未决。我们认为遗传多态和表观遗传变化之间的相互作用 决定基因表达和可能的信使核糖核酸的加工，在药物成瘾中起着关键作用。大号 部分可疑的成瘾易感基因含有CpG岛，其甲基化代表 主要的表观遗传机制。遗传和表观遗传因素都可能导致成瘾易感性 以及由于滥用药物而发生的生理变化。我们将在尸检中研究这些因素。 来自迈阿密大脑捐赠银行的组织，包含大约500个来自可卡因和其他药物的样本 施虐者和年龄匹配的对照组。这个资料库可以在相关的大脑中进行遗传和表观遗传学研究 与上瘾有关的地区。CpG甲基化可以在基因的两个等位基因之间随机发生 (以总体表达水平表示)，或以等位基因选择性的方式。后者导致等位基因 表达失衡(AEI)，它代表了基因和基因的精确和定量的表型 表观遗传顺式作用因子。这使我们能够解决几个问题。CpG是如何孤岛的 甲基化在不同的大脑区域是不同的，个体之间的差异是什么？甲基化是否会影响 基因表达，替代启动子的使用，还是替代剪接？滥用药物的后果是什么？ 在候选基因的CpG岛甲基化，在相关的大脑区域？表观生成和遗传因素 对临床状态(成瘾)有影响吗？在这个项目中，我们以含有CpG岛的基因为目标 与成瘾有关，关注生物胺途径，编码合成和分解代谢酶， 囊泡和突触再摄取转运体和受体(MAOA，MAOB，COMT，TH，DAT，NET，VMAT2， DRD2、CHRNA4)。我们已经开发了高通量工具来测量遗传和表观遗传学 对信使核糖核酸和蛋白质表达的贡献，以及选择性剪接。我们的化验是针对等位基因的， 能够评估等位基因表达中的遗传和表观遗传因素，这是评估 各因素的量化影响。这一新方法应用于解剖学定义的脑组织 从吸毒者和控制者那里，有可能对吸毒者的作用和相互作用有重要的洞察力 遗传和表观遗传因素之间的关系，并增加了我们对成瘾易感性的理解。

Drug addiction is a complex disorder with a strong genetic component, while the role of epigenetic factors remains unresolved. We propose that the interplay between genetic polymorphisms and epigenetic changes determines gene expression and possibly mRNA processing, serving a critical role in drug addiction. A large portion of suspected addiction susceptibility genes harbors CpG islands, methylation of which represents a main epigenetic mechanism. Both genetic and epigenetic factors likely contribute to addiction susceptibility and physiological changes occurring as a result of substance abuse. We will study these factors in autopsy tissues from the Miami Brain Endowment Bank, containing ~approximately 500 samples from cocaine and other drug abusers and age-matched controls. This repository enables genetic and epigenetic studies in relevant brain regions involved in addiction. CpG methylation can occur randomly between the two allele of a gene (represented in overall expression level), or in an allele-selective fashion. The latter causes an allelic expression imbalance (AEI), which represents a precise and quantitative phenotype for both genetic and epigenetic cis-acting factors. This permits us to address several questions. How does CpG island methylation vary across brain regions, and what is the variability among individuals? Does methylation affect gene expression, alternate promoter usage, or alternative splicing? What is the effect of substance abuse on CpG island methylation in candidate genes, in relevant brain regions? Do epigentic and genetic factors contribute to clinical status (addiction)? In this project, we target genes harboring CpG islands that are implicated in addiction, focusing on biogenic amine pathways, encoding synthetic and catabolic enzymes, vesicular and synaptic reuptake transporters, and receptors (MAOA, MAOB, COMT, TH, DAT, NET, VMAT2, DRD2, CHRNA4). We have developed high-throughput tools for measuring the genetic and epigenetic contribution to mRNA and protein expression, and alternative splicing. Our assays are allele-specific, enabling the evaluation of genetic and epigenetic factors in allelic expression, a powerful tool for assessing the quantitative impact of each factor. This novel approach, applied to anatomically defined brain tissues from drug addicts and controls, has the potential to yield significant insight into the role of and interplay between genetic and epigenetic factors, and add to our understanding of susceptibility to addiction.