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存活至关重要。动态的 养分环境在整个自然界中无处不在，包括 多细胞生物中的微生物和组织壁ni。无法适应会导致细胞死亡， 发育缺陷和疾病。 自适应细胞反应通常是通过基因表达程序快速诱导的变化来实现的。 实现此目的的理想机制是通过修饰染色质。尽管有这些知识， 染色质修饰有助于代谢可塑性的机制在很大程度上尚未探索。作为 这样，许多广泛的生物学问题仍未得到解决：代谢信号通路如何交流 用染色质调节基因表达？代谢环境如何修饰染色质以促进 自适应基因表达和坐标细胞分裂？染色质修饰如何影响能量 在发育节目中的代谢可塑性？代谢记忆如何传播？ 我们提出的研究很重要，因为它将在必要时建立染色质修饰剂 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，该事件是协调代谢可塑性的，并且是自适应细胞的核心 回答。我们的中心假设是染色质修饰符将营养感应途径连接到 适当的适应性，增殖和发育所需的代谢基因调节。我们计划 使用包括代谢同步的创新方法以及 单细胞染色质和代谢分析。我们非常适合进行这些研究，因为我们的研究 是第一个证明代谢信号下游的染色质重塑复合物功能 调节与细胞分裂和发育时机的代谢的途径。 通过实现我们的研究目标，我们期望以下结果：综合 确定与能量代谢途径调整的组蛋白修饰；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；鉴定新型染色质介导的代谢记忆机制 和多样化。这些研究将大大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生物的生存力，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