The Role of Chromatin in Metabolic Homeostasis

染色质在代谢稳态中的作用

• 批准号: 10629441
• 负责人: Ashby J. Morrison
• 金额: $ 47.27万
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629441
• 关键词: Achievement; Biological; Cell Death; Cell division; Cell physiology; Cells; Chromatin; Chromatin Remodeling Factor; Communication; Defect; Development; Diabetes Mellitus; Disease; Energy Metabolism; Energy Metabolism Pathway; Environment; Epigenetic Process; Event; Failure; Gene Expression; Gene Expression Regulation; Goals; Growth; Growth and Development function; Heart Diseases; Homeostasis; Investigation; Knowledge; Link; Malignant Neoplasms; Mediating; Memory; Metabolic; Metabolic dysfunction; Metabolism; Nature; Nutrient; Organism; Outcome; Pathway interactions; Proliferating; Public Health; Research; Role; Signal Pathway; Tissues; cell growth; chromatin modification; detection of nutrient; epigenetic therapy; fitness; histone modification; innovation; microorganism; novel; programs; response

The coordination of cellular function with the environment is essential for adaptation and survival. 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. 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. As such, many broad biological questions remain unanswered: How do metabolic signaling pathways communicate with chromatin to regulate gene expression? How does the metabolic environment modify chromatin to facilitate adaptive gene expression and coordinate cell division? How do chromatin modifications influence energy metabolism plasticity during developmental programming? How is metabolic memory propagated? 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 alterations and metabolic dysfunction in developmental abnormalities and disease states. Our broad research goal is to define the chromatin modification events that coordinate metabolic plasticity and are central to adaptive cellular responses. Our central hypothesis is that chromatin modifiers link nutrient sensing pathways to metabolic gene regulation required for proper fitness, proliferation, and development. We plan to investigate this hypothesis using innovative approaches that include metabolic-synchronization, as well as single-cell chromatin and metabolic profiling. We are ideally suited to carry out these studies, as our research was the first to demonstrate that a chromatin remodeling complex functions downstream of metabolic signaling pathways to regulate coordinate metabolism with cell division and developmental timing. Through achievement of our research goals we expect the following outcomes: Comprehensive determination of histone modifications that are in tune with energy metabolism pathways; determination of the relationship between nutrient sensing pathways and chromatin; characterization of the tissue-specific metabolic requirements during development; identification of novel chromatin-mediated mechanisms for metabolic memory and diversification. These investigations will greatly enhance our knowledge of metabolic plasticity mechanisms and how they contribute to cellular and organismal viability, development and disease.

细胞功能与环境的协调对于适应和生存至关重要。动态 营养环境在自然界中无处不在，包括竞争生长环境 多细胞生物体中繁殖的微生物和组织生态位。不适应可能会导致细胞死亡， 发育缺陷和疾病。 适应性细胞反应通常是通过基因表达程序的快速可诱导变化来实现的。 实现这一点的理想机制是通过对染色质的修饰。尽管有这样的知识，但 染色质修饰促进代谢可塑性的机制在很大程度上尚不清楚。AS 这样，许多广泛的生物学问题仍然没有答案：新陈代谢信号通路是如何沟通的 用染色质来调节基因表达？代谢环境如何改变染色质以促进 适应性基因表达和协调细胞分裂？染色质修饰如何影响能量 发育规划中的新陈代谢可塑性？新陈代谢记忆是如何传播的？ 我们提出的研究具有重要意义，因为它将在必要时建立染色质修饰物 代谢动态平衡的组成部分，并作为研究表观遗传变化和 发育异常和疾病状态下的代谢功能障碍。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，是适应性细胞的中心 回应。我们的中心假设是染色质修饰物将营养感知途径连接到 新陈代谢基因调节是健康、增殖和发育所必需的。我们计划 使用包括代谢同步在内的创新方法来研究这一假说，以及 单细胞染色质和代谢图谱。我们非常适合进行这些研究，因为我们的研究 是第一个证明染色质重塑复合体在代谢信号下游发挥作用的人 调节新陈代谢的途径与细胞分裂和发育时间相协调。 通过实现我们的研究目标，我们预计会有以下结果： 与能量代谢途径相协调的组蛋白修饰的测定 营养感应通路与染色质的关系；组织特异性代谢的特征 发育过程中的需求；新的染色质介导的代谢记忆机制的鉴定 和多样化。这些研究将极大地提高我们对代谢可塑性机制的认识 以及它们如何对细胞和生物体的生存、发育和疾病做出贡献。