Chromatin Regulation by Mammalian SIRT7 in Aging and Disease

Sirtuin酶家族的成员是基因组稳定性、应激和免疫调节的重要调节剂。 反应，以及影响人类健康和疾病的代谢程序。SIRT6和SIRT7是 与哺乳动物密切相关的调节基本核过程的sirtuins。这些酶催化 染色质上的高选择性组蛋白脱乙酰化反应，从而去除重要的乙酰基标记 来自特定的赖氨酸残基。正确调节染色质上组蛋白乙酰化模式对于 建立专门的染色质状态，控制基因表达，DNA修复等过程， DNA复制。组蛋白乙酰化模式的失调，如SIRT6或SIRT7被激活时所发生的。 因此，失活的蛋白质可以在细胞和整个生物体水平上产生病理后果。 事实上，SIRT6具有许多与衰老，代谢和癌症相关的功能。通过 相反，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）去乙酰化酶，在调节致癌基因中起关键作用 转化程序和肿瘤形成。我们的初步研究提供了证据 SIRT7在影响癌症和脂肪肝的细胞代谢过程中的表观遗传功能 疾病本研究旨在阐明SIRT7在这些过程中的作用和机制。在 此外，我们的初步数据显示，SIRT7的特异性底物H3K18Ac也可以被 通过SIRT6脱乙酰化。我们将询问SIRT 6和SIRT 6之间如何协调H3 K18 Ac的脱乙酰化作用 SIRT7在特定的基因组和生理环境中的作用，以及这些sirtuins是否提供了代偿性作用。 保护免受有缺陷的H3K18Ac脱乙酰化的病理后果的机制。 在目标1中，我们将阐明SIRT7在致癌转化中的新作用和机制， 癌症通路我们将使用遗传和生物化学策略来研究SIRT7与 致癌Myc转录因子在调节癌细胞翻译能力、增殖和 生存此外，我们还将探讨SIRT7是否会影响肿瘤细胞的致癌转化效率。 培养物中的原代细胞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 在人类中，这种疾病非常普遍，容易导致肝功能衰竭和癌症。但其 对潜在的机制知之甚少。我们将联合收割机结合分子、基因组和细胞 研究SIRT7突变小鼠的方法，以研究其分子机制， SIRT7影响脂肪肝的发病机制。越来越多的证据表明内质网（ER） 脂肪肝的发生、发展过程中的应激反应。我们将检验SIRT7 通过减弱ER应激的致病作用以及通过直接 调节参与脂质代谢的基因的表达。 在目标3中，我们将研究H3K18Ac中SIRT6和SIRT7之间的功能相互作用和重叠。 体内平衡和癌细胞生物学。我们将采用新产生的系统来抑制这两种酶 同时，使用双RNAi策略和双突变小鼠，并测定基因组，细胞和 全生物表型。总之，这些研究应该阐明基本的染色质机制 SIRT6和SIRT7作为治疗靶点的潜力。

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.