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。为 例如，细胞有非凡的能力感知不同的(即营养丰富的或有限的)环境和 相应地对他们的能量代谢和增殖能力进行重新编程。动态的营养环境是 在自然界中无处不在，包括繁殖的微生物和 多细胞生物体中的组织生态位。不适应可能会导致细胞死亡、发育缺陷和 疾病。事实上，能量代谢的改变是许多病理的主要因素，包括 癌症、心血管疾病和糖尿病，这些疾病加起来占美国所有死亡人数的三分之二。 适应性细胞反应通常是通过基因表达的快速可诱导变化来实现的 程序。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， 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。 事实上，许多广泛的生物学问题仍然没有得到回答：能量代谢的灵活性是否促进了 通过染色质调节代谢基因的表达？营养感知通路是如何连接到 这些染色质调节剂的功能是什么？染色质调节的代谢基因表达是否影响 对细胞分裂的承诺？这些染色质修饰剂是否影响所需的能量代谢可塑性 在发展规划期间。 我们的初步数据表明，染色质重构体通过(重新)定位来调节转录 核小体是代谢信号通路的中心组成部分。染色质重塑的破坏 导致代谢基因表达、耗氧量、细胞分裂和胚胎缺陷 发展。我们的中心假设是染色质修饰物将营养感知途径连接到 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 是定义协调新陈代谢可塑性的染色质修饰事件，并且是适应性的中心 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 在不同的生物背景下。通过实现我们的研究目标，我们期望有以下几点 结果：确定新的能量代谢表观遗传调节因子；确定两者之间的关系 在营养感应通路和染色质之间；对染色质调节代谢的识别 细胞分裂要求.能量新陈代谢所需染色质修饰的测定 发展。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，并作为一个平台来研究表观遗传调控 发育异常和疾病状态下的代谢功能。

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.