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.

Public Health Relevance

The proposed research is relevant to public health because it will define the role of a chromatin remodeling in the regulation of metabolic homeostasis important for cell growth and developmen. As such, this research will develop new opportunities for epigenetic therapies in diseases emanating from metabolic dysfunction, such as diabetes, heart disease, and cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1-CB-E (50)R)
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Carter, Anthony D
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Stanford University
Schools of Arts and Sciences
United States
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Zhou, Coral Y; Johnson, Stephanie L; Lee, Laura J et al. (2018) The Yeast INO80 Complex Operates as a Tunable DNA Length-Sensitive Switch to Regulate Nucleosome Sliding. Mol Cell 69:677-688.e9
Rhee, Siyeon; Chung, Jae I; King, Devin A et al. (2018) Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease. Nat Commun 9:368
Gowans, Graeme J; Schep, Alicia N; Wong, Ka Man et al. (2018) INO80 Chromatin Remodeling Coordinates Metabolic Homeostasis with Cell Division. Cell Rep 22:611-623
Beckwith, Sean L; Schwartz, Erin K; GarcĂ­a-Nieto, Pablo E et al. (2018) The INO80 chromatin remodeler sustains metabolic stability by promoting TOR signaling and regulating histone acetylation. PLoS Genet 14:e1007216
Morrison, Ashby J (2017) Genome maintenance functions of the INO80 chromatin remodeller. Philos Trans R Soc Lond B Biol Sci 372: