The Role of Chromatin in Metabolic Homeostasis

染色质在代谢稳态中的作用

• 批准号: 9983876
• 负责人: Ashby J. Morrison
• 金额: $ 6.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9983876
• 关键词: Achievement; Biological; Biological Models; Cardiovascular Diseases; Cell Death; Cell division; Cell physiology; Cells; Cessation of life; Chromatin; Chromatin Remodeling Factor; Data; Defect; Development; Diabetes Mellitus; Disease; Embryonic Development; Energy Metabolism; Environment; Epigenetic Process; Event; Failure; Gene Expression; Gene Expression Regulation; Genetic Transcription; Goals; Growth; Heart Diseases; Homeostasis; Knowledge; Lead; Link; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolic dysfunction; Mus; Nature; Nucleosomes; Nutrient; Organism; Outcome; Oxygen Consumption; Pathology; Pathway interactions; Positioning Attribute; Proliferating; Public Health; Regulation; Research; Role; Signal Pathway; Tissues; Yeasts; cell growth; chromatin modification; chromatin remodeling; detection of nutrient; epigenetic regulation; epigenetic therapy; fitness; flexibility; innovation; microorganism; novel; programs; response

The coordination of cellular function with the environment is essential for adaptation and survival. For example, cells have remarkable ability to sense diverse (i.e. nutrient-rich or -limiting) environments and reprogram their energy metabolism and proliferative capacity accordingly. Dynamic nutrient environments are ubiquitous throughout nature and include competitive growth environments of proliferating microorganisms and tissue niches in multicellular organisms. Failure to adapt can lead to cell death, developmental defects, and disease. Indeed, energy metabolism alterations are a major contributing factor for many pathologies, including cancer, cardiovascular disease, and diabetes, which together account for two-thirds of all deaths in the U.S. Adaptive cellular responses are often achieved by rapid inducible changes in gene expression programs. An ideal mechanism to achieve this is through modification of chromatin. Despite this knowledge, the mechanisms by which chromatin modification contributes to metabolic plasticity remain largely unexplored. Indeed, many broad biological questions remain unanswered: Is energy metabolism flexibility facilitated through chromatin regulation of metabolic gene expression? How are nutrient sensing pathways connected to the function of these chromatin regulators? Does chromatin-regulated metabolic gene expression influence commitment to cell division? Do these chromatin modifiers influence energy metabolism plasticity required during developmental programming. Our preliminary data suggests chromatin remodelers, which regulate transcription by (re)positioning nucleosomes, are central components of metabolic signaling pathways. Disruption of chromatin remodeling results in defects in metabolic gene expression, oxygen consumption, cell division, and embryonic development. Our central hypothesis is that chromatin modifiers link nutrient sensing pathways to metabolic gene regulation required for fitness, proliferation and development. Our broad research goal is to define chromatin modifications events that coordinate metabolic plasticity and are central to adaptive cellular responses. Our varied experimental approach is innovative because it leverages the power of diverse eukaryotic model systems, namely yeast and mice, to investigate fundamental conserved metabolic pathways within different biological contexts. Through achievement of our research goal we expect the following outcomes: Identification of novel epigenetic regulators of energy metabolism; determination of the relationship between nutrient sensing pathways and chromatin; recognition of the chromatin-regulated metabolic requirements for cell division; determination of chromatin modification required for energy metabolism during development. Our proposed research is significant because it will establish chromatin modifiers as necessary components of metabolic homeostasis, and serve as a platform to investigate epigenetic regulation of metabolic function in developmental abnormalities and disease states.

细胞功能与环境的协调对于适应和生存至关重要。为 例如，细胞具有感知不同（即营养丰富或限制）环境的显着能力， 重新编程它们的能量代谢和增殖能力。动态营养环境是 在自然界中普遍存在，包括增殖微生物的竞争性生长环境， 多细胞生物体中的组织小生境。不能适应会导致细胞死亡，发育缺陷， 疾病事实上，能量代谢改变是许多病理学的主要促成因素，包括 癌症、心血管疾病和糖尿病，这些疾病共占美国所有死亡人数的三分之二。 适应性细胞反应通常通过基因表达的快速诱导变化来实现 程序.实现这一点的理想机制是通过染色质的修饰。尽管有这些知识， 染色质修饰促进代谢可塑性的机制在很大程度上仍未被探索。 事实上，许多广泛的生物学问题仍然没有答案：能量代谢的灵活性是否得到促进 通过染色质调节代谢基因的表达？营养感应途径是如何与 这些染色质调节因子的功能染色质调节的代谢基因表达是否影响 致力于细胞分裂？这些染色质修饰剂是否影响所需的能量代谢可塑性 在发展规划中。 我们的初步数据表明，染色质重塑，调节转录（重新）定位 核小体是代谢信号传导途径的中心组分。染色质重塑的破坏 导致代谢基因表达、耗氧量、细胞分裂和胚胎发育缺陷。 发展我们的中心假设是染色质修饰剂将营养传感途径与 健康、增殖和发育所需的代谢基因调控。我们广泛的研究目标 是定义染色质修饰事件，协调代谢可塑性，是适应性的核心， 细胞反应。我们多样化的实验方法是创新的，因为它利用了多样化的力量， 真核生物模型系统，即酵母和小鼠，以研究基本的保守代谢途径 在不同的生物学背景下。通过实现我们的研究目标，我们期望以下几点 结果：鉴定新的能量代谢表观遗传调节因子;确定 营养感应途径和染色质之间的关系;识别染色质调节的代谢 细胞分裂的要求;细胞分裂过程中能量代谢所需的染色质修饰的测定 发展我们提出的研究是有意义的，因为它将建立必要的染色质修饰剂 代谢稳态的组成部分，并作为一个平台，调查表观遗传调节 发育异常和疾病状态中的代谢功能。