Chromatin Regulation by Mammalian SIRT7 in Aging and Disease

Sirtuin酶家族的成员是基因组稳定性、应激反应的重要调节者 影响人类健康和疾病的反应和新陈代谢计划。SIRT6和SIRT7是 与哺乳动物密切相关的调节基本核过程的sirtuin。这些酶催化 染色质上高选择性的组蛋白去乙酰化反应，从而去除重要的乙酰基标记 从特定的赖氨酸残基。适当调节组蛋白在染色质上的乙酰化模式对于 建立专门的染色质状态，控制基因表达、DNA修复和 DNA复制。组蛋白乙酰化模式的失调，当SIRT6或SIRT7 因此，被灭活的病毒会在细胞和整个生物体层面上产生病理后果。 事实上，SIRT6具有许多与衰老、新陈代谢和癌症相关的功能。通过 相比之下，人们对SIRT7的了解要少得多。我们最近表明，SIRT7是一种高度选择性的 H3K18Ac(乙酰化组蛋白H3赖氨酸18)脱乙酰酶在调控致癌中的关键作用 转化计划和肿瘤的形成。现在，我们的初步研究提供了其他证据 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。本提案旨在阐明SIRT7在这些过程中的作用和机制。在……里面 此外，我们的初步数据显示，SIRT7的特异性底物H3K18Ac也可以 由SIRT6脱乙酰化。我们将询问H3K18Ac的脱乙酰基在SIRT6和SIRT6之间是如何协调的 SIRT7在特定的基因组和生理环境中，以及这些sirtuins是否提供补偿 保护H3K18Ac脱乙酰化缺陷的病理后果的机制。 在目标1中，我们将阐明SIRT7在肿瘤转化和修复中的新作用和新机制。 癌症途径。我们将使用遗传和生化策略来研究SIRT7和SIRT7之间的新联系 致癌Myc转录因子在调节癌细胞翻译能力、增殖和 生死存亡。此外，我们还将询问SIRT7是否会影响肺癌的致癌转化效率 培养中的原代细胞和小鼠的总体肿瘤敏感性。 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……里面 在人类中，这种疾病非常普遍，容易发生肝功能衰竭和癌症。然而，它的 人们对潜在的机制知之甚少。我们将结合分子、基因组和细胞 结合SIRT7突变小鼠的研究，探讨SIRT7基因的分子机制 SIRT7影响脂肪肝的发病机制。越来越多的证据表明内质网(ER) 应激在脂肪肝的发生和发展中的作用。我们将检验SIRT7的假设 通过减轻内质网应激的致病效应以及通过直接 调节脂代谢相关基因的表达。 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 动态平衡与癌细胞生物学。我们将使用新产生的系统来灭活这两种酶。 同时，使用双RNAi策略和双突变小鼠，并检测基因组、细胞和 整个生物体的表型。总之，这些研究应该阐明染色质的基本机制。 以及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.