Chromatin and metabolic regulation of plasticity in a predatory nematode

项目概述：环境可以从一个基因型中引出多种表型，这是一种现象， 称为发育（表型）可塑性。早期的环境条件可以使 对成人健康的影响，如胎儿接触有毒化学品或营养不良。然而，我们也可以 利用发育可塑性对我们有益，包括学习，适应性免疫，以及饮食和 锻炼的尽管可塑性对生殖健康和生殖健康的重要性，我们仍然缺乏一个机制， 了解它是如何工作的。我的实验室试图通过应用生物化学 表型可塑性的有机体模型的方法。从我的工作和其他证据指向组蛋白 修饰是饮食和表型之间的关键中介。我们实验室的中心假设是， 组蛋白修饰的代谢底物实际上是传递饮食的信号分子， 表型。确定这些途径是必要的，以了解如何穷人-或过于丰富-饮食有助于 疾病 从历史上看，可塑性已经在有限的分子工具的非模式生物中进行了研究。与此相反， 模式生物的发展传统上集中在不变条件下的不变过程。在我 在实验室中，我们使用了一种动物模型，该模型（1）在实验上易于处理，（2）表现出极端形式的可塑性， 来揭示饮食和表型之间的联系。太平洋棱纹线虫表达两种 成年人可能的嘴型-杂食性或食菌性-取决于他们所经历的饮食条件 作为青少年。在我的博士后研究中，我开发了P. pacificus作为模型系统，以探索染色质在 可塑性这项工作导致了组蛋白4（H4）乙酰化控制口形发育的发现。的 我的独立实验室的研究建立在这个结果的基础上，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， 决定太平洋对虾口形的调控机制。首先，我们将确定哪些代谢途径 受到诱导任一形态的饮食的影响。其次，我们将确定这些途径如何进入组蛋白- 激素水平，或两者兼而有之。第三，我们将研究H4乙酰化如何诱导转录。 控制嘴型的基因为了解决这些问题，我们联合收割机技术从染色质 生物化学与公正的全基因组方法。我们的长期目标是应用从 这些实验是为了预防或治疗人类饮食影响的疾病，如II型糖尿病，肥胖症， 和心脏病。

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.