Chromatin Regulation by Mammalian SIRT7 in Aging and Disease

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、应激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。这些酶催化染色质的高选择性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标记。组蛋白乙酰化模式在染色质的适当调节是必不可少的建立专门的染色质状态，控制过程，如基因表达，DNA修复和DNA复制。因此，当SIRT6或SIRT7失活时发生的组蛋白乙酰化模式的失调可以在细胞和整个生物体水平上具有病理后果。事实上，SIRT6具有许多与衰老，代谢和癌症相关的功能。相比之下，对SIRT7的了解要少得多。我们最近发现SIRT7是一种高度选择性的H3K18Ac（乙酰化组蛋白H3赖氨酸18）脱乙酰酶，在调节致癌转化程序和肿瘤形成中起着关键作用。现在，我们的初步研究为SIRT7在影响癌症和脂肪肝疾病的细胞代谢过程中的额外表观遗传功能提供了证据。本研究旨在阐明SIRT7在这些过程中的作用和机制。此外，我们的初步数据显示，SIRT7的特异性底物H3K18Ac也可以被SIRT6脱乙酰化。我们将询问在特定的基因组和生理环境中，SIRT6和SIRT7之间如何协调H3K18Ac的脱乙酰化，以及这些sirtuins是否提供了保护H3K18Ac脱乙酰化缺陷的病理后果的补偿机制。 在目标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和致癌Myc转录因子在调节癌细胞翻译能力、增殖、 和生存此外，我们将询问SIRT7是否影响培养物中原代细胞的致癌转化效率和小鼠的总体肿瘤易感性。 在目标2中，我们将描述SIRT7在预防脂肪肝疾病中的作用和机制。在人类中，这种疾病非常普遍，容易导致肝功能衰竭和癌症。然而，其基本机制知之甚少。我们将结合联合收割机的分子，基因组和细胞的方法与SIRT7突变小鼠的研究，以探讨SIRT7影响脂肪肝发病机制的分子机制。越来越多的证据表明内质网（ER）应激在脂肪肝的发生和发展中起作用。我们将测试SIRT7通过减弱ER应激的致病作用以及直接调节参与脂质代谢的基因表达来预防脂肪肝疾病的假设。 在目标3中，我们将研究SIRT6和SIRT7在H3K18Ac稳态和癌细胞生物学中的功能相互作用和重叠。我们将采用新产生的系统，使用双RNAi策略和双突变小鼠同时抑制两种酶，并测定基因组、细胞和整个生物体的表型。总之，这些研究应该阐明人类生理学和疾病中的基本染色质机制以及SIRT6和SIRT7作为治疗靶点的潜力。

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.