Chromatin Regulation by Mammalian SIRT7 in Aging and Disease

哺乳动物 SIRT7 在衰老和疾病中的染色质调节

• 批准号: 8814993
• 负责人: Katrin F Chua
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814993
• 关键词: Acetylation; Address; Aging; Attenuated; Biochemical; Biological Assay; Biology of Aging; Cancer Biology; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Chromatin; DNA Repair; DNA biosynthesis; Data; Deacetylase; Deacetylation; Development; Disease; Ensure; Enzymes; Epigenetic Process; Essential Genes; Family; Fatty Liver; Gene Expression; Genes; Genetic; Genome Stability; Genomics; Goals; Health; Heart Diseases; Hematopoietic Neoplasms; Histone Acetylation; Histone Deacetylation; Histone H3; Homeostasis; Human; Inflammatory; Link; Lipids; Liver; Liver Failure; Liver diseases; Lysine; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of thyroid; Metabolic; Metabolic Diseases; Metabolism; Molecular; Molecular Biology; Molecular Mechanisms of Action; Mus; Mutant Strains Mice; Nuclear; Oncogenic; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pattern; Phenotype; Physiological; Physiology; Play; Population; Predisposition; Process; Property; RNA Interference; Reaction; Regulation; Regulatory Pathway; Research; Role; Signal Transduction; Sirtuins; System; Testing; Therapeutic; Tumorigenicity; Veterans; Whole Organism; Work; biological adaptation to stress; cancer cell; endoplasmic reticulum stress; human disease; insight; lipid metabolism; malignant breast neoplasm; member; mouse model; novel; prevent; programs; stress management; targeted treatment; therapeutic target; transcription factor; tumor; tumor metabolism

DESCRIPTION (provided by applicant): Members of the Sirtuin family of enzymes are important regulators of genomic stability, stress responses, and metabolic programs that impact on human health and disease. SIRT6 and SIRT7 are closely related mammalian sirtuins that regulate fundamental nuclear processes. These enzymes catalyze highly selective histone deacetylation reactions at chromatin, whereby important acetyl marks are removed from specific lysine residues. Proper regulation of histone acetylation patterns at chromatin is essential for establishing specialized chromatin states that control processes such as gene expression, DNA repair, and DNA replication. Dysregulation of histone acetylation patterns, as occurs when SIRT6 or SIRT7 are inactivated, can therefore have pathological consequences at the cellular and whole organism levels. Indeed, SIRT6 has numerous demonstrated functions relevant for aging, metabolism, and cancer. By contrast, much less is understood about SIRT7. We recently showed that SIRT7 is a highly selective H3K18Ac (acetylated histone H3 lysine 18) deacetylase that plays a pivotal role in modulating oncogenic transformation programs and tumor formation. Now, our preliminary studies provide evidence for additional epigenetic functions of SIRT7 in cellular metabolic processes that impact on both cancer and fatty liver disease. This proposal aims to elucidate the role and mechanisms of SIRT7 in these processes. In addition, our preliminary data reveal that the specific substrate of SIRT7, H3K18Ac, can also be deacetylated by SIRT6. We will ask how deacetylation of H3K18Ac is coordinated between SIRT6 and SIRT7 in specific genomic and physiologic settings, and whether these sirtuins provide compensatory mechanisms that protect against pathological consequences of defective H3K18Ac deacetylation. In Aim 1, we will elucidate novel roles and mechanisms of SIRT7 in oncogenic transformation and cancer pathways. We will use genetic and biochemical strategies to study a new link between SIRT7 and the oncogenic Myc transcription factor in regulating cancer cell translational capacity, proliferation, and survival. In addition, we will ask whether SIRT7 influences the efficiency of oncogenic transformation of primary cells in culture and overall tumor susceptibility in mice. In Aim 2, we will characterize the role and mechanisms of SIRT7 in preventing fatty liver disease. In humans, this disease is highly prevalent and predisposes to liver failure and cancer. However, its underlying mechanisms are poorly understood. We will combine molecular, genomic, and cellular approaches with studies of SIRT7 mutant mice to investigate the molecular mechanisms through which SIRT7 influence fatty liver disease pathogenesis. Growing evidence implicates endoplasmic reticulum (ER) stress in the development and progression of fatty liver disease. We will test the hypothesis that SIRT7 prevents fatty liver disease by attenuating the pathogenic effects of ER stress, as well as by directly regulating the expression of genes involved in lipid metabolism. In Aim 3, we will examine the functional interplay and overlap between SIRT6 and SIRT7 in H3K18Ac homeostasis and cancer cell biology. We will employ newly generated systems to inactivate both enzymes simultaneously, using double RNAi strategies and double mutant mice, and assay genomic, cellular and whole organism phenotypes. Together, these studies should elucidate fundamental chromatin mechanisms in human physiology and disease and the potential of SIRT6 and SIRT7 as therapeutic targets.

描述（由申请人提供）： Sirtuin酶家族的成员是影响人类健康和疾病的基因组稳定性，压力反应和代谢程序的重要调节剂。 SIRT6和SIRT7是调节基本核过程的密切相关的哺乳动物Sirtuins。这些酶催化了高度选择性的组蛋白脱乙酰化反应，从而从特定的赖氨酸残基中去除重要的乙酰基痕迹。适当调节染色质组蛋白乙酰化模式对于建立控制基因表达，DNA修复和DNA复制等专业染色质状态至关重要。因此，在SIRT6或SIRT7被灭活时，组蛋白乙酰化模式的失调可能在细胞和整个生物体水平上产生病理后果。实际上，SIRT6具有许多与衰老，代谢和癌症有关的功能。相比之下，关于SIRT7的理解少得多。我们最近表明SIRT7是高度选择性的H3K18AC（乙酰化组蛋白H3赖氨酸18）脱乙酰基酶，在调节致癌转化程序和肿瘤形成方面起着关键作用。现在，我们的初步研究为SIRT7在影响癌症和脂肪肝病的细胞代谢过程中的其他表观遗传功能提供了证据。该建议旨在阐明SIRT7在这些过程中的作用和机制。此外，我们的初步数据表明，SIRT7（H3K18AC）的特定底物也可以被SIRT6脱乙酰基6。我们将询问特定基因组和生理环境中SIRT6和SIRT7之间H3K18AC的脱乙酰基化是如何协调的，以及这些SIRTUINS是否提供了防止缺陷H3K18AC脱乙酰化的病理后果的补偿机制。 在AIM 1中，我们将阐明SIRT7在致癌转化和癌症途径中的新作用和机制。我们将使用遗传和生化策略来研究SIRT7与致癌MYC转录因子之间的新联系，以调节癌细胞的转化能力，增殖，增殖， 和生存。此外，我们将询问SIRT7是否会影响原代细胞在培养物和小鼠整体肿瘤易感性中的致癌效率。 在AIM 2中，我们将表征SIRT7在预防脂肪肝病中的作用和机制。在人类中，这种疾病高度流行，并且易于肝衰竭和癌症。但是，其基本机制知之甚少。我们将将分子，基因组和细胞方法与SIRT7突变小鼠的研究相结合，以研究SIRT7影响脂肪肝病发病机理的分子机制。越来越多的证据表明，脂肪肝病的发育和进展中内质网（ER）应力。我们将检验以下假设：SIRT7通过减弱ER应激的致病作用以及直接调节涉及脂质代谢的基因的表达来阻止脂肪肝病。 在AIM 3中，我们将研究H3K18AC稳态和癌细胞生物学中SIRT6和SIRT7之间的功能相互作用和重叠。我们将使用新生成的系统同时使用双RNAi策略和双突变小鼠同时灭活这两种酶，并分析基因组，细胞和整个生物体表型。总之，这些研究应阐明人类生理和疾病中的基本染色质机制，以及SIRT6和SIRT7作为治疗靶标的潜力。