Studying epigenetic pathways in brain function and social behavior using ants

利用蚂蚁研究大脑功能和社会行为的表观遗传途径

• 批准号: 8755972
• 负责人: Roberto Bonasio
• 金额: $ 240万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8755972
• 关键词: Address; Adult; Affect; Animals; Ants; Attention; Behavior; Behavioral; Biological Models; Brain; Castes; Cell Maintenance; Cells; Chemical Structure; Chromatin; Chromatin Structure; Chromosomes; Cues; DNA Methylation; Development; Drosophila melanogaster; Epigenetic Process; Exhibits; Experimental Models; Foundations; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genome; Health; Hormonal; Human; Impaired cognition; Individual; Insecta; Intervention; Investigation; Laboratory Animals; Mental Retardation; Mental disorders; Molecular; Neurosciences; Pathway interactions; Phenotype; Process; RNA Interference; Regulation; Role; Social Behavior; Social Environment; Social Interaction; Stimulus; System; Time; Untranslated RNA; addiction; fascinate; histone modification; novel; public health relevance; social; social model; social organization; tool

DESCRIPTION (provided by applicant): It is becoming increasingly apparent that the molecular machinery that is responsible for the epigenetic regulation of gene expression and maintenance of cell identity has fundamental roles in the development and function of the animal brain. Considering that the disruption of epigenetic processes such as DNA methylation and histone modifications can cause mental retardation, cognitive decline, addiction, and various psychiatric disorders, revealing the mechanistic connection between epigenetics, brain function, and behavior has far- reaching implications not only for neuroscience but also for human health. To better understand how epigenetic processes affect brain function, I will develop and exploit a new model system: the ant Harpegnathos saltator. Ant workers and queens exhibit starkly distinct behaviors without differences in their genetic composition; therefore, by definition, epigenetic mechanisms must contribute to activate and repress caste-specific behaviors in the appropriate individuals. Many of the ants' sophisticated behaviors are predictable, stereotypic within each caste, and often modulated by external cues that can be controlled experimentally, such as social context and chemosensory stimuli. Moreover, unlike Drosophila melanogaster, ants have a fully functional DNA methylation system. For these reasons, ants constitute an ideal experimental system to investigate epigenetics in the brain, especially in the context of social behavior. Among ants, Harpegnathos is particularly suited as a laboratory animal because any worker can, under the proper conditions, be converted into a functional pseudo-queen in a fascinating process that offers a natural experimental paradigm to study epigenetic plasticity in the adult brain and, at the same time, will allow us to develop genetic approaches that are unattainable in most other social insects. The proposed studies consist of a coordinated and ambitious investigation on the molecular mechanisms of caste determination, behavior, and social organization in ants, with particular attention to the regulation of gene expression by epigenetic processes. We will begin from an in-depth characterization of the changes in the brain transcriptome that accompany the behavioral switch from Harpegnathos workers to pseudo-queens. We will identify the gene networks that are responsible for the observed changes in phenotype and dissect the regulatory layer superimposed on these networks, with a focus on known and emerging epigenetic pathways, including DNA methylation, histone modifications, and regulation by noncoding RNAs. To address the functional significance of the genes and pathways identified, we will develop novel genetic tools in Harpegnathos and utilize already established experimental approaches such as RNA interference, pharmacological intervention, hormonal treatments, and manipulation of the social environment. This project will firmly establish Harpegnathos as a model social insect and will lay the foundations to understand at a molecular level the epigenetic regulation of brain function and social behavior.

描述（由申请人提供）：越来越明显的是，负责基因表达的表观遗传调节和细胞特性维持的分子机制在动物脑的发育和功能中具有重要作用。考虑到DNA甲基化和组蛋白修饰等表观遗传过程的破坏可能导致智力迟钝、认知能力下降、成瘾和各种精神疾病，揭示表观遗传学、脑功能和行为之间的机制联系不仅对神经科学而且对人类健康都具有深远的意义。 为了更好地了解表观遗传过程如何影响大脑功能，我将开发和利用一个新的模型系统：蚂蚁Harpegnathos saltator。工蚁和蚁后表现出截然不同的行为，而它们的遗传组成没有差异;因此，根据定义，表观遗传机制必须有助于激活和抑制适当个体的种姓特异性行为。许多蚂蚁的复杂行为是可预测的，每个种姓内的刻板印象，并经常受到可以通过实验控制的外部线索的调节，例如社会环境和化学感觉刺激。此外，与果蝇不同，蚂蚁有一个功能齐全的DNA甲基化系统。由于这些原因，蚂蚁构成了研究大脑表观遗传学的理想实验系统，特别是在社会行为的背景下。在蚂蚁中，Harpegnathos特别适合作为实验室动物，因为在适当的条件下，任何工人都可以在一个迷人的过程中转化为功能性的伪女王，这为研究成年大脑的表观遗传可塑性提供了一个自然的实验范式，同时，将使我们能够开发大多数其他社会昆虫无法实现的遗传方法。 拟议的研究包括一个协调和雄心勃勃的调查种姓的决定，行为和社会组织的分子机制在蚂蚁，特别注意表观遗传过程的基因表达的调节。我们将开始从一个深入的表征的变化，在大脑转录组，伴随着行为转换，从竖琴工人的伪皇后。我们将确定负责观察到的表型变化的基因网络，并剖析叠加在这些网络上的调控层，重点关注已知和新兴的表观遗传途径，包括DNA甲基化，组蛋白修饰和非编码RNA的调控。为了解决所确定的基因和途径的功能意义，我们将在Harpegnathos中开发新的遗传工具，并利用已经建立的实验方法，如RNA干扰，药物干预，激素治疗和操纵社会环境。该项目将坚定地确立Harpegnathos作为一种模式社会昆虫，并将奠定基础，以了解在分子水平上的大脑功能和社会行为的表观遗传调控。

项目成果

Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2.

• DOI: 10.1038/s41556-018-0084-5
• 发表时间: 2018-05
• 期刊: Nature cell biology
• 影响因子: 21.3
• 作者: Choi J;Lee K;Ingvarsdottir K;Bonasio R;Saraf A;Florens L;Washburn MP;Tadros S;Green MR;Busino L
• 通讯作者: Busino L