Chromatin and metabolic regulation of plasticity in a predatory nematode

项目摘要：环境可以从一个单一的基因中引发多种表型，一种现象 称为发育(表型)可塑性。生命早期的环境条件可能会持续 对成人健康的影响，例如胎儿接触有毒化学品或营养不良。然而，我们也可以 利用发育可塑性为我们带来好处，包括学习、适应性免疫以及饮食和 锻炼身体。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械的 了解它是如何工作的。我的实验室试图通过应用生物化学来解决这一知识差距 方法建立表型可塑性的生物模型。我的工作和其他人的证据表明，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将饮食传递到 表型。确定这些途径对于了解贫穷或过度丰富的饮食是如何促成 疾病。 历史上，人们用有限的分子工具在非模型生物中研究可塑性。相比之下， 模式生物的发展传统上侧重于在不变的条件下不变的过程。在我的 在实验室，我们使用的动物模型(1)实验上容易驯服，(2)表现出极端形式的可塑性， 以揭示饮食和表型之间的联系。和平Pristionchus线虫表达两种中的一种 成人可能的口腔形态-杂食性或细菌性-取决于他们所经历的饮食条件 作为青少年。在我的博士后生涯中，我开发了P.pacphaus作为一个模型系统，以探索染色质在 可塑性。这项工作导致了组蛋白4(H4)乙酰化控制口型发育的发现。这个 我的独立实验室的研究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。 在最初的五年里，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规定。首先，我们将确定哪些代谢途径是 受引起任何一种变形的饮食的影响。第二，我们将确定这些通路如何进入组蛋白- 修饰，荷尔蒙水平，或者两者兼而有之。第三，我们将研究H4乙酰化如何诱导转录 控制口型的基因。为了解决这些问题，我们结合了染色质的技术 生物化学与无偏见的全基因组方法。我们的长期目标是将从 这些实验旨在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.