Chromatin and metabolic regulation of plasticity in a predatory nematode

捕食性线虫可塑性的染色质和代谢调节

• 批准号: 10715689
• 负责人: Michael S Werner
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-25 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715689
• 关键词: Acetylation; Address; Adolescent; Adult; Affect; Animal Model; Biochemical; Biochemistry; Biological Models; Cardiovascular Diseases; Chromatin; Development; Diet; Disease; Environment; Exhibits; Exposure to; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genotype; Goals; Health; Heart Diseases; Histones; Hormones; Human; Knowledge; Laboratories; Learning; Life; Malnutrition; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Molecular; Nematoda; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral cavity; Organism; Pathway interactions; Phenotype; Poison; Postdoctoral Fellow; Process; Regulation; Reproductive Health; Research; Role; Signal Transduction; Signaling Molecule; Techniques; Work; adaptive immunity; developmental plasticity; diet and exercise; dietary; experience; experimental study; genome-wide; histone modification; insight; model organism; nutrition; prenatal exposure; prevent; programs; reproductive fitness; tool; Acetylation; Address; Adolescent; Adult; Affect; Animal Model; Biochemical; Biochemistry; Biological Models; Cardiovascular Diseases; Chromatin; Development; Diet; Disease; Environment; Exhibits; Exposure to; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genotype; Goals; Health; Heart Diseases; Histones; Hormones; Human; Knowledge; Laboratories; Learning; Life; Malnutrition; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Molecular; Nematoda; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral cavity; Organism; Pathway interactions; Phenotype; Poison; Postdoctoral Fellow; Process; Regulation; Reproductive Health; Research; Role; Signal Transduction; Signaling Molecule; Techniques; Work; adaptive immunity; developmental plasticity; diet and exercise; dietary; experience; experimental study; genome-wide; histone modification; insight; model organism; nutrition; prenatal exposure; prevent; programs; reproductive fitness; tool

PROJECT SUMMARY: The environment can elicit multiple phenotypes from a single genotype, a phenomenon referred to as developmental (phenotypic) plasticity. Early-life environmental conditions can have lasting consequences on adult health, such as fetal exposure to toxic chemicals or malnutrition. However, we can also use developmental plasticity to our benefit, including learning, adaptive immunity, and the benefits of diet and exercise. Despite the importance of plasticity for reproductive fitness and health, we still lack a mechanistic understanding of how it works. My laboratory seeks to address this gap in knowledge by applying biochemical methods to an organismal model of phenotypic plasticity. Evidence from my work and others points to histone modifications as key intermediaries between diet and phenotype. The central hypothesis of our laboratory is that the metabolic substrates of histone modifications are, in effect, the signaling molecules which relay diet to phenotype. Identifying these pathways is necessary to understand how poor – or overly rich – diets contribute to disease. Historically, plasticity has been studied in non-model organisms with limited molecular tools. In contrast, development in model organisms has traditionally focused on invariant processes in invariant conditions. In my lab, we use an animal model that is both (1) experimentally tractable and (2) exhibits an extreme form of plasticity, to reveal the connections between diet and phenotype. Pristionchus pacificus nematodes express one of two possible mouth forms in adults – omnivore or bacterivore – depending on the dietary conditions they experience as juveniles. In my postdoc, I developed P. pacificus as a model system to explore the role of chromatin in plasticity. This work led to the discovery that histone 4 (H4) acetylation controls mouth-form development. The research in my independent laboratory builds off of this result, and seeks to determine the molecular pathways from diet to metabolism, and from metabolism to gene expression. In the first five years, we will investigate the upstream metabolic signals and downstream mechanisms of gene regulation which determine P. pacificus mouth-form. First, we will determine which metabolic pathways are affected by diets that induce either morph. Second, we will determine how these pathways feed into histone- modifications, hormone levels, or both. Third, we will investigate how H4 acetylation induces transcription of genes that control mouth-form. To address these questions, we combine techniques from chromatin biochemistry with unbiased genome-wide approaches. Our long-term goal is to apply the insight gained from these experiments to prevent, or treat, dietary-influenced diseases in humans such as type-II diabetes, obesity, and heart disease.

项目摘要：环境可以从单个基因型中引起多种表型，即一种现象 称为发育（表型）可塑性。早期生活的环境条件可能持久 对成人健康的后果，例如胎儿暴露于有毒化学物质或营养不良。但是，我们也可以 利用发展可塑性为我们的利益，包括学习，适应性免疫学以及饮食的好处和 锻炼。尽管可塑性对于生殖健身和健康很重要，但我们仍然缺乏机械 了解其工作原理。我的实验室试图通过应用生化来解决知识中的这一差距 表型可塑性有机模型的方法。我工作和其他人的证据指向组蛋白 修饰作为饮食和表型之间的关键中介。我们实验室的中心假设是 实际上，组蛋白修饰的代谢底物是传达饮食的信号分子 表型。确定这些途径是必须了解饮食饮食有多么贫穷或过于富裕的途径有必要 疾病。 从历史上看，可塑性已经在具有有限的分子工具的非模型生物中进行了研究。相比之下， 传统上，模型生物的开发集中在不变条件下的不变过程上。在我的 实验室，我们使用的是（1）实验可行的动物模型，并且（2）表现出极端形式的可塑性， 揭示饮食与表型之间的联系。 Pristionchus pacificus nematodes表达了两个 根据他们经历的饮食状况，成人可能的口腔形式 - 杂食或细菌 作为少年。在我的博士后，我开发了P. Pacificus作为模型系统，以探索染色质的作用 可塑性。这项工作导致发现Hisstone 4（H4）乙酰化控制口腔形式的发展。这 我的独立实验室的研究是建立在这一结果的基础上，并试图确定分子途径 从饮食到新陈代谢，从新陈代谢到基因表达。 在最初的五年中，我们将研究基因上游代谢信号和下游机制 确定太平洋假单胞菌口形式的调节。首先，我们将确定哪些代谢途径是 受影响变体的饮食影响。其次，我们将确定这些途径如何馈入Hisstone- 修改，骑马水平或两者兼而有之。第三，我们将研究H4乙酰化如何影响 控制口腔形式的基因。为了解决这些问题，我们结合了染色质的技术 具有无偏基因组方法的生物化学。我们的长期目标是应用从中获得的见解 这些实验以预防或治疗饮食影响的疾病，例如II型糖尿病，肥胖症， 和心脏病。