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）： 不良的童年经历与以后生活中的精神疾病风险增加有关，尤其是抑郁症。最近的研究表明，在早期的压力经历后，一个人是否会受到5-羟色胺转运蛋白基因多态性的影响（5-HTT：5-Hydroxyptamine Transporter）。尚不清楚早期应力在成年中增加抑郁症的风险的分子机制，但假定包括基因表达的表观遗传编程。这支研究人员团队在小鼠中开发了一种创新的基因 - 环境相互作用筛选（GXE屏幕），该筛选首次允许通过早期不良环境通过这种动物模型来检查通过早期不良环境来检查表观遗传编程的分子机制的研究。使用GXE屏幕的目的是表明，不良饲养环境对焦虑相关行为的影响是通过5-HTT中的突变调节的，以模仿人类在人类中看到的早期应力与5-HTT之间的相互作用。这些发现表明，该模型中涉及的分子机制与人类抑郁症的病因有关。该建议旨在应用一种新型的高通量甲基化分析技术来从此屏幕上对小鼠进行整个基因组表观遗传分析。实验有望鉴定通过饲养环境和小鼠中5-HTT表观遗传调节的基因。这些基因将成为人类严重抑郁症的候选敏感性基因，并将作为诊所的潜在诊断和治疗靶标。