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Dynamic and stable regulation of aggression through DNA methylation

通过 DNA 甲基化动态稳定地调节攻击行为

基本信息

批准号：
9064228
负责人：
GENE E ROBINSON
金额：
$ 19.83万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-07 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9064228
关键词：
Adult African Age Aggressive behavior Bees Behavior Behavioral Behavioral Model Biological Assay Biological Models Brain DNA DNA Methylation Development Disease Drosophila genus Environment Environmental Risk Factor Enzymes Epigenetic Process European Exhibits Exposure to Gene Expression Genes Genomics Genotype Health High-Throughput Nucleotide Sequencing Homologous Gene Honey Human Immunoprecipitation Individual Inherited Injection of therapeutic agent Justice Laboratories Law Enforcement Lead Link Mammals Measures Mediating Medicine Methods Methylation Modeling Modification Molecular Organism Pattern Personality Disorders Pheromone RNA Interference Regulation Research Role Site Small Interfering RNA Societies Stimulus Substance abuse problem System Testing Thymine DNA Glycosylase Variant Work behavioral response behavioral study demethylation diagnostic biomarker differential expression epigenome experience interest knock-down methylation pattern methylome oxidation programs psychologic research study response therapeutic target trait translocase

项目摘要

DESCRIPTION (provided by applicant): Aggressive behavior is a damaging influence in our society, since by definition it is intended to inflict physical or psychological harm. In humans, growing up in a socially adverse environment can strongly influence the development of aggressive tendencies, and genotypic variation can also predispose individuals to aggression. DNA methylation is an epigenetic modification that exists in relatively stable patterns, but can change at specific loci in response to the environment. This stable/dynamic duality potentially places DNA methylation at the regulatory interface between genotypic and environmental influences on behavior. This proposal will investigate whether DNA methylation mediates the influences of genotype and environment on aggression in the honey bee, a model that exhibits well-characterized aggressive behaviors, and unlike the fruit fly, has a fully functional, mammalian-like methylation system. Strains of bees differ in their aggressiveness, and our prior work has shown that the highly aggressive African honey bee (AHB) shows differences in brain gene expression and DNA methylation from the less aggressive European honey bee (EHB). In addition, EHB provoked to aggression by exposure to alarm pheromone show expression changes in some of the same genes. We will test the hypothesis that DNA methylation serves as a stable epigenetic mark regulating inherited differences in aggression, while also acting as a dynamic regulator responding to environmental stimuli that promote aggression. In mammals, DNA methylation patterns can be modulated through active DNA demethylation, which is mediated by ten-eleven translocase (TET) and thymine DNA glycosylase (TDG) enzymes. To determine whether a TET/TDG-dependent DNA demethylation mechanism exists in bees and regulates aggression, TDG will be knocked down in the bee brain using RNA interference (RNAi); preliminary results indicate a ca. 20% knockdown. We will measure DNA demethylation and aggression in the TDG knockdown bees, as well as the accumulation of oxidized 5-methylcytosine derivatives, which are known intermediates of active DNA methylation in other organisms. To explore whether DNA methylation also establishes aggression as a stable trait associated with genotype, we will examine the stability of DNA methylation patterns at aggression-related genes in AHB and EHB. Lastly, we will compare methylation patterns at aggression-related genes between the hereditary and environmentally-induced aggressive contexts. We expect to observe similar methylation patterns between the two, supporting our hypothesis that DNA methylation is a regulator underlying both genotypic and environmental effects on aggression.

描述（由申请人提供）：攻击性行为对我们的社会具有破坏性影响，因为根据定义，攻击性行为旨在造成身体或心理伤害。对于人类来说，在不利的社会环境中成长会强烈影响攻击倾向的发展，而基因型变异也会使个体容易产生攻击行为。 DNA甲基化是一种表观遗传修饰，以相对稳定的模式存在，但可以根据环境在特定位点发生变化。这种稳定/动态的二元性可能将 DNA 甲基化置于基因型和环境对行为影响之间的调节界面。该提案将研究DNA甲基化是否介导基因型和环境对蜜蜂攻击性的影响，这种模型表现出明确的攻击性行为，并且与果蝇不同，它具有功能齐全、类似哺乳动物的甲基化系统。蜜蜂品种的攻击性不同，我们之前的研究表明，攻击性较高的非洲蜜蜂 (AHB) 与攻击性较低的欧洲蜜蜂 (EHB) 在大脑基因表达和 DNA 甲基化方面存在差异。此外，通过暴露于警报信息素而引发攻击性的EHB显示出一些相同基因的表达变化。我们将检验这样的假设：DNA 甲基化作为稳定的表观遗传标记，调节攻击性的遗传差异，同时也充当响应促进攻击性的环境刺激的动态调节器。在哺乳动物中，DNA 甲基化模式可以通过主动 DNA 去甲基化来调节，这种去甲基化是由 10-11 易位酶 (TET) 和胸腺嘧啶 DNA 糖基化酶 (TDG) 介导的。为了确定蜜蜂中是否存在 TET/TDG 依赖性 DNA 去甲基化机制并调节攻击性，将使用 RNA 干扰 (RNAi) 敲低蜜蜂大脑中的 TDG；初步结果表明大约。 20% 击倒率。我们将测量 TDG 敲除蜜蜂中的 DNA 去甲基化和攻击性，以及氧化 5-甲基胞嘧啶衍生物的积累，这些衍生物是其他生物体中活跃 DNA 甲基化的已知中间体。为了探讨 DNA 甲基化是否也将攻击性建立为与基因型相关的稳定特征，我们将检查 AHB 和 EHB 中攻击性相关基因的 DNA 甲基化模式的稳定性。最后，我们将比较遗传性和环境引起的攻击性环境中攻击性相关基因的甲基化模式。我们期望观察到两者之间相似的甲基化模式，支持我们的假设，即 DNA 甲基化是基因型和环境对攻击行为影响的调节因子。