The Role of Chromatin in Metabolic Homeostasis

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普遍存在，包括竞争性生长环境， 增殖微生物和多细胞生物体中的组织小生境。不能适应会导致细胞死亡， 发育缺陷和疾病。 适应性细胞反应通常通过基因表达程序中的快速诱导变化来实现。 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。作为 因此，许多广泛的生物学问题仍然没有答案：代谢信号通路如何沟通 用染色质来调节基因表达代谢环境如何改变染色质， 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 代谢可塑性在发育规划中的作用代谢记忆是如何传播的？ 我们提议的研究很重要，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的平台， 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 协调代谢可塑性的染色质修饰事件是适应性细胞的核心， 应答我们的中心假设是染色质修饰剂将营养感应途径与 代谢基因调节所需的适当健身，增殖和发展。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物在代谢信号下游发挥作用的人 调节协调代谢与细胞分裂和发育时间的途径。 通过实现我们的研究目标，我们期望取得以下成果： 确定与能量代谢途径一致的组蛋白修饰; 营养感应途径和染色质之间的关系;组织特异性代谢的表征 发展过程中的要求;新的染色质介导的代谢记忆机制的鉴定 和多样化。这些研究将大大提高我们对代谢可塑性机制的认识 以及它们如何促进细胞和生物体的生存能力、发育和疾病。

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.