Epigenetic Programming by Early Gene-Environment Interactions

通过早期基因-环境相互作用进行表观遗传编程

• 批准号: 7172015
• 负责人: CORNELIUS T GROSS
• 金额: $ 16.2万
• 依托单位: EUROPEAN MOLECULAR BIOLOGY LABORATORY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7172015
• 关键词: behavioral /social science research tag; behavioral genetics; biological models; chromatin; early experience; epigenetics; gene environment interaction; gene expression; gene expression profiling; genetic mapping; genetic promoter element; genetic screening; genetically modified animals; immunoprecipitation; laboratory mouse; major depression; mental health epidemiology; methylation; microarray technology; psychological models

DESCRIPTION (provided by applicant): Adverse childhood experiences are associated with increased risk of mental illness later in life, especially depression. Recent studies show that whether a person develops major depression following early stressful experiences is influenced by a polymorphism in the serotonin transporter gene (5-HTT: 5-hydroxytryptamine transporter). The molecular mechanisms by which early stress increases risk for depression in adulthood is not known, but is presumed to include epigenetic programming of gene expression. This team of researchers has developed an innovative gene-environment interaction screen (GxE screen) in mouse that allows for the first time a study examining the molecular mechanisms underlying epigenetic programming by early adverse environment through genetic manipulation of this animal model. Using the GxE screen the intent is to show that the effects of adverse rearing environment on anxiety-related behavior are modulated by mutations in 5-HTT in a way that mimics the interaction between early stress and 5-HTT seen in humans. These findings suggest that the molecular mechanisms involved in this model are relevant to the etiology of human depression. This proposal seeks to apply a novel high-throughput methvlation profiling technique to perform whole genome epigenetic profiling of mice from this screen. Experiments promise to identify genes that are epigenetically regulated by rearing environment and 5-HTT in mouse. These genes will become candidate susceptibility genes for major depression in humans and will serve as potential diagnostic and therapeutic targets in clinic.

描述（由申请人提供）： 不良的童年经历与日后患精神疾病（尤其是抑郁症）的风险增加有关。最近的研究表明，一个人在早期的压力经历后是否会患上重度抑郁症，受到血清素转运蛋白基因（5-HTT：5-羟色胺转运蛋白）多态性的影响。早期压力增加成年期抑郁症风险的分子机制尚不清楚，但推测包括基因表达的表观遗传编程。该研究小组在小鼠中开发了一种创新的基因-环境相互作用屏幕（GxE屏幕），首次允许研究通过对该动物模型进行遗传操作来检查早期不利环境导致的表观遗传编程的分子机制。使用 GxE 筛选的目的是表明，不良饲养环境对焦虑相关行为的影响是通过 5-HTT 突变来调节的，其方式模仿了人类早期压力和 5-HTT 之间的相互作用。这些发现表明该模型涉及的分子机制与人类抑郁症的病因学相关。该提案旨在应用一种新型高通量甲基化分析技术来对来自该筛选的小鼠进行全基因组表观遗传分析。实验有望鉴定出受小鼠饲养环境和 5-HTT 表观遗传调控的基因。这些基因将成为人类重度抑郁症的候选易感基因，并作为临床潜在的诊断和治疗靶点。