Efficient glucose metabolism is critical for maintaining cellular viability. Under normal nutrient and oxygen conditions, glucose is converted to pyruvate, which enters the mitochondria to be used for oxidative phosphorylation to produce ATP. Under hypoxia or nutrient stress, metabolism is switched to glycolysis, increasing lactate production and reducing mitochondrial respiration through a mechanism that involves the transcription factor Hif11. This switch is critical to maintain cells during periods of starvation or hypoxia;furthermore, recent studies indicate that modulating this switch could be beneficial under a situation of chronic glucose imbalance, such as in patients with Type II diabetes. Little is known whether chromatin plays a role in carbohydrate flux. The yeast Sir2 protein is an NAD-dependent histone deacetylase that senses the metabolic status of the cell and functions as a chromatin silencer to promote lifespan and genomic stability. Seven mammalian Sir2 homologs have been found (SIRT1-7), but their functions remain to be fully elucidated. Recently, we discovered that the mammalian SIRT6 is a chromatin factor that influences glucose metabolism and DNA repair. In mice, SIRT6-deficiency provokes a profound and lethal hypoglycemia which culminates in accelerated death. At the cellular level, SIRT6 inactivation leads to increased cellular glucose uptake, higher lactate production and decreased mitochondrial activity. Preliminary results indicate that SIRT6 can regulate expression of several key genes in these metabolic pathways. In this context, SIRT6 appears to function at chromatin to attenuate a Hif11 transcriptional nutrient response. SIRT6 binds to Hif11 and acts as a histone H3 lysine9 (H3K9) deacetylase to inhibit expression of Hif11-target gene promoters. The main goal of this proposal is to test specifically whether SIRT6 regulates nutrient stress, functioning as a chromatin modifier to modulate multiple genes involved in switching glucose metabolism away of glycolysis and towards mitochondrial respiration.

Public Health Relevance

In order to survive under conditions of nutrient stress, cells trigger an adaptive response, re-routing glucose in order to produce enough energy to sustain their survival. The yeast protein Sir2 functions as a modulator of lifespan, sensing nutrient availability to adapt the cellular metabolic activity;while recent studies indicate that some of the mammalian homologs (termed sirtuins) play a role in stress resistance and metabolic homeostasis, their precise molecular functions remain to be fully elucidated. In this proposal, we will test the hypothesis that one of these homologs, SIRT6, modulates glucose metabolism as a critical regulator of multiple metabolic genes, and as such might influence ageing and age related diseases like diabetes and cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Genetics B Study Section (MGB)
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Carter, Anthony D
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Massachusetts General Hospital
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Etchegaray, Jean-Pierre; Chavez, Lukas; Huang, Yun et al. (2015) The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine. Nat Cell Biol 17:545-57
Kugel, Sita; Feldman, Jessica L; Klein, Mark A et al. (2015) Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer. Cell Rep 13:479-488
Singh, Indrabahadur; Ozturk, Nihan; Cordero, Julio et al. (2015) High mobility group protein-mediated transcription requires DNA damage marker ?-H2AX. Cell Res 25:837-50
Choi, Jee-Eun; Mostoslavsky, Raul (2014) Sirtuins, metabolism, and DNA repair. Curr Opin Genet Dev 26:24-32
Silberman, Dafne M; Ross, Kenneth; Sande, Pablo H et al. (2014) SIRT6 is required for normal retinal function. PLoS One 9:e98831
Sebastián, Carlos; Mostoslavsky, Raul (2014) Untangling the fiber yarn: butyrate feeds Warburg to suppress colorectal cancer. Cancer Discov 4:1368-70
Kugel, Sita; Mostoslavsky, Raul (2014) Chromatin and beyond: the multitasking roles for SIRT6. Trends Biochem Sci 39:72-81
Toiber, Debra; Erdel, Fabian; Bouazoune, Karim et al. (2013) SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol Cell 51:454-68
Etchegaray, Jean-Pierre; Zhong, Lei; Mostoslavsky, Raul (2013) The histone deacetylase SIRT6: at the crossroads between epigenetics, metabolism and disease. Curr Top Med Chem 13:2991-3000
Jiang, Hong; Khan, Saba; Wang, Yi et al. (2013) SIRT6 regulates TNF-? secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496:110-3

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