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

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：环境可以从单一基因型引发多种表型，这是一种现象 称为发育（表型）可塑性。生命早期的环境条件可以具有持久性。 对成人健康的影响，例如胎儿接触有毒化学物质或营养不良。 利用发育可塑性为我们带来好处，包括学习、适应性免疫以及饮食和饮食的好处 尽管可塑性对于生殖健康和健康很重要，但我们仍然缺乏一种机制。 我的实验室致力于通过应用生化来弥补这一知识空白。 我的工作和其他人的工作证据指向组蛋白。 我们实验室的中心假设是，修饰是饮食和表型之间的关键中介。 组蛋白修饰的代谢底物实际上是将饮食传递给 识别这些途径对于了解不良或过度丰富的饮食如何造成影响是必要的。 疾病。 历史上，可塑性是在非模型生物中用有限的分子工具进行研究的。 模式生物的发展传统上侧重于不变条件下的不变过程。 实验室中，我们使用的动物模型既（1）在实验上易于处理，（2）表现出极端的可塑性， 揭示饮食与表型之间的联系，Pristionchus pacificus 线虫表达以下两种之一。 成人可能的口腔形态——杂食动物或细菌动物——取决于他们经历的饮食条件 在我的博士后阶段，我开发了太平洋对虾作为模型系统来探索染色质的作用。 这项工作导致了组蛋白 4 (H4) 乙酰基控制口形发育的发现。 我的独立实验室的研究以这一结果为基础，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。 前五年，我们将研究基因的上游代谢信号和下游机制 决定太平洋对虾口型的调节首先，我们将确定哪些代谢途径。 其次，我们将确定这些途径如何进入组蛋白。 第三，我们将研究 H4 乙酰化如何诱导转录。 为了解决这些问题，我们结合了染色质技术。 我们的长期目标是应用从全基因组方法中获得的见解。 这些实验旨在预防或治疗人类饮食影响的疾病，例如二型糖尿病、肥胖症、 和心脏病。