The histone deacetylase SIRT6 functions as a co-repressor of Hif1 alpha in glucos

组蛋白脱乙酰酶 SIRT6 在葡萄糖中充当 Hif1 α 的共阻遏物

• 批准号: 8664883
• 负责人: Raul Mostoslavsky
• 金额: $ 33.29万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664883
• 关键词: Acetylation; Acute; Age; Attenuated; Binding; Binding Sites; Carbohydrates; Cell physiology; Cells; Cellular Stress; Cessation of life; Chromatin; Chronic; DNA Repair; Deacetylase; Diabetes Mellitus; Disease; Epigenetic Process; Gene Targeting; Genes; Genome Stability; Glucose; Glycolysis; Glycolysis Inhibition; Goals; Histone Deacetylase; Histone H3; Histones; Homeostasis; Homologous Gene; Hypoglycemia; Hypoxia; Hypoxia-Responsive Elements; Longevity; Luciferases; Malignant Neoplasms; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Oxidative Phosphorylation; Oxygen; Patients; Phenotype; Play; Production; Proteins; Pyruvate; Regulation; Reporter; Resistance; Respiration; Role; Secondary to; Sirtuins; Starvation; Stress; System; Testing; Transcriptional Activation; Yeasts; age related; anaerobic glycolysis; biological adaptation to stress; chromatin immunoprecipitation; detection of nutrient; glucose metabolism; glucose uptake; inhibitor/antagonist; knock-down; loss of function; oxidation; promoter; response; small molecule; transcription factor; vector; yeast protein

DESCRIPTION (provided by applicant): 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.

描述（由申请方提供）：有效的葡萄糖代谢对于维持细胞活力至关重要。在正常的营养和氧气条件下，葡萄糖转化为丙酮酸，丙酮酸进入线粒体用于氧化磷酸化以产生ATP。在缺氧或营养胁迫下，代谢转换为糖酵解，通过涉及转录因子Hif 11的机制增加乳酸产生并减少线粒体呼吸。这种开关对于在饥饿或缺氧期间维持细胞至关重要;此外，最近的研究表明，调节这种开关在慢性葡萄糖失衡的情况下可能是有益的，例如在II型糖尿病患者中。很少有人知道染色质是否在碳水化合物流动中起作用。酵母Sir 2蛋白是NAD依赖性组蛋白脱乙酰酶，其感测细胞的代谢状态并作为染色质沉默物发挥作用以促进寿命和基因组稳定性。已经发现了七种哺乳动物Sir 2同源物（SIRT 1 -7），但它们的功能仍有待充分阐明。最近，我们发现哺乳动物SIRT 6是一种影响葡萄糖代谢和DNA修复的染色质因子。在小鼠中，SIRT 6缺乏引起严重和致命的低血糖，最终导致加速死亡。在细胞水平，SIRT 6失活导致细胞葡萄糖摄取增加，乳酸产生增加和线粒体活性降低。初步结果表明，SIRT 6可以调节这些代谢途径中几个关键基因的表达。在这种情况下，SIRT 6似乎在染色质中起作用，以减弱Hif 11转录营养反应。SIRT 6与Hif 11结合，并作为组蛋白H3赖氨酸9（H3 K9）脱乙酰酶抑制Hif 11靶基因启动子的表达。该提案的主要目标是专门测试SIRT 6是否调节营养应激，作为染色质修饰剂调节参与将葡萄糖代谢从糖酵解转向线粒体呼吸的多个基因。

项目成果

Sirtuins, metabolism, and DNA repair.

• DOI: 10.1016/j.gde.2014.05.005
• 发表时间: 2014-06
• 期刊: CURRENT OPINION IN GENETICS & DEVELOPMENT
• 影响因子: 4
• 作者: Choi, Jee-Eun;Mostoslavsky, Raul
• 通讯作者: Mostoslavsky, Raul

Recent progress in the biology and physiology of sirtuins.

• DOI: 10.1038/nature08197
• 发表时间: 2009-07-30
• 期刊: Nature
• 影响因子: 64.8
• 作者: Finkel T;Deng CX;Mostoslavsky R
• 通讯作者: Mostoslavsky R

SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling.

• DOI: 10.1016/j.molcel.2013.06.018
• 发表时间: 2013-08-22
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Toiber, Debra;Erdel, Fabian;Bouazoune, Karim;Silberman, Dafne M.;Zhong, Lei;Mulligan, Peter;Sebastian, Carlos;Cosentino, Claudia;Martinez-Pastor, Barbara;Giacosa, Sofia;D'Urso, Agustina;Naeaer, Anders M.;Kingston, Robert;Rippe, Karsten;Mostoslavsky, Raul
• 通讯作者: Mostoslavsky, Raul

Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE.

• DOI: 10.1371/journal.pone.0007897
• 发表时间: 2009-11-19
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bruzzone S;Fruscione F;Morando S;Ferrando T;Poggi A;Garuti A;D'Urso A;Selmo M;Benvenuto F;Cea M;Zoppoli G;Moran E;Soncini D;Ballestrero A;Sordat B;Patrone F;Mostoslavsky R;Uccelli A;Nencioni A
• 通讯作者: Nencioni A

Fine tuning our cellular factories: sirtuins in mitochondrial biology.

• DOI: 10.1016/j.cmet.2011.05.004
• 发表时间: 2011-06-08
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Zhong L;Mostoslavsky R
• 通讯作者: Mostoslavsky R