The Role of Chromatin in Metabolic Homeostasis Supplemental

染色质在代谢稳态中的作用补充剂

• 批准号: 10797761
• 负责人: Ashby J. Morrison
• 金额: $ 9.49万
• 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/10797761
• 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。动态的 营养环境在自然界中无处不在，包括竞争性生长环境 多细胞生物体中增殖的微生物和组织生态位。不适应会导致细胞死亡， 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诱导变化来实现的。 实现这一目标的理想机制是通过染色质修饰。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。作为 因此，许多广泛的生物学问题仍未得到解答：代谢信号通路如何沟通 与染色质调节基因表达？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 发育编程过程中的代谢可塑性？代谢记忆是如何传播的？ 我们提出的研究意义重大，因为它将根据需要建立染色质修饰剂 代谢稳态的组成部分，并作为研究表观遗传改变和 发育异常和疾病状态中的代谢功能障碍。我们广泛的研究目标是定义 协调代谢可塑性并对适应性细胞至关重要的染色质修饰事件 回应。我们的中心假设是染色质修饰剂将营养感应途径与 适当的健康、增殖和发育所需的代谢基因调节。我们计划 使用包括代谢同步在内的创新方法研究这一假设，以及 单细胞染色质和代谢分析。我们非常适合开展这些研究，因为我们的研究 第一个证明染色质重塑复合物在代谢信号下游发挥作用 调节代谢与细胞分裂和发育时间协调的途径。 通过实现我们的研究目标，我们期望获得以下成果： 综合 确定与能量代谢途径相一致的组蛋白修饰；的确定 营养感应途径与染色质之间的关系；组织特异性代谢的表征 开发过程中的要求；鉴定新的染色质介导的代谢记忆机制 和多元化。这些研究将极大地增强我们对代谢可塑性机制的了解 以及它们如何促进细胞和有机体的活力、发育和疾病。

项目成果

Cancer cell metabolism connects epigenetic modifications to transcriptional regulation.

• DOI: 10.1111/febs.16032
• 发表时间: 2022-03
• 期刊: The FEBS journal
• 作者: Morrison AJ