The Role of Chromatin in Metabolic Homeostasis

点击翻译按钮获取中文摘要

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.