Molecular Mechanisms of Mammalian SIRT6 Function

哺乳动物 SIRT6 功能的分子机制

• 批准号: 9282767
• 负责人: Katrin F Chua
• 金额: $ 37.44万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282767
• 关键词: Affect; Aging; Attenuated; Biochemical; Biological; Biology of Aging; Cancer Biology; Cancer cell line; Cell Aging; Cell physiology; Cells; Cellular biology; Centromere; Chromatin; Chromatin Structure; Chromosomal Rearrangement; Chromosome Segregation; DNA; DNA Repair; DNA Sequence; DNA Transposable Elements; Data; Deacetylase; Defect; Disease; Elements; Enzymes; Epigenetic Process; Event; Family; Fibroblasts; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genomic Instability; Genomic approach; Genomics; Goals; Heterochromatin; Homeostasis; Human; Human Genome; Impairment; Junk DNA; Link; Longevity; Lysine; Maintenance; Malignant Neoplasms; Mammalian Cell; Metabolic; Metabolic Diseases; Mitosis; Modeling; Molecular; Mus; Neurodegenerative Disorders; Nuclear; Oncogenic; Pathogenesis; Pathology; Phenotype; Process; RNA Interference; Regulation; Regulator Genes; Repression; Research; Role; Satellite DNA; Sirtuins; Somatic Cell; Telomere Maintenance; Testing; Therapeutic Intervention; Tissues; Transcript; Transcriptional Silencer Elements; Translating; Untranslated RNA; age related; cancer cell; functional decline; healthy aging; human disease; insight; mammalian genome; new therapeutic target; novel; overexpression; programs; public health relevance; senescence; telomere; tumor metabolism; tumor progression

 DESCRIPTION (provided by applicant): Our research seeks to understand how chromatin regulatory mechanisms influence nuclear and epigenetic programs, and how de-regulation of these mechanisms contributes to aging and disease. SIRT6 is a chromatin regulatory factor in the sirtuin family of enzymes. SIRT6-deficiency in mice leads to shortened lifespan and phenotypes associated with aging, cancer, and metabolism. Conversely, SIRT6 over-expression in mice protects against metabolic disease and extends lifespan. Thus, studying SIRT6 function promises to elucidate fundamental mechanisms that underlie healthy aging and longevity. Previously, we showed that SIRT6 selectively regulates specific chromatin marks associated with epigenetic and gene-regulatory functions. We linked chromatin regulation by SIRT6 to key nuclear processes that impact on aging and cancer, including telomere maintenance, DNA repair, and aging-associated gene expression changes. Here, we focus on new functions of SIRT6 in chromatin silencing mechanisms that are deregulated in aging. We propose molecular, genomic, and functional studies to study the role of SIRT6 in maintaining heterochromatin silencing at repetitive DNA elements, and ask how impaired silencing is linked to aging-associated cellular dysfunction. In Aim 1, we will study the molecular mechanisms of SIRT6 in heterochromatin silencing of repetitive satellite DNA elements at centromeres. Defects in pericentric heterochromatin are observed in the contexts of both aging and cancer. We will characterize the biochemical activity of SIRT6 at pericentric chromatin and study downstream higher order chromatin changes. Our studies will provide insights for cancer cell biology, where SIRT6 loss may contribute to cancer progression, and for human somatic cells, where SIRT6 may guard against cellular senescence or age-dependent decline in epigenetic plasticity. In Aim 2, we will characterize the functional effects of heterochromatin maintenance by SIRT6 on cellular homeostasis. We will test the hypotheses that pericentric heterochromatin defects trigger abnormal mitoses, chromosome segregation defects, and cellular senescence, or facilitate the oncogenic process of cellular immortalization. We will also examine functional interplay between SIRT6 and other SIRT enzymes in these processes. These studies should elucidate how heterochromatin breakdown is translated into cellular phenotypes or functional decline that contributes to aging and disease. In Aim 3, we will investigate the role of SIRT6 in heterochromatin maintenance at another class of repetitive DNA elements that are deregulated in aging and cancer - endogenous retrotransposable elements. We will ask if impaired silencing of these elements is associated with genomic instability that can affect cellular function, or to aberrant transcription of aging-related genes. Together, these studies should provide insights into fundamental chromatin mechanisms in aging biology.

 描述（由适用提供）：我们的研究旨在了解染色质调节机制如何影响核和表观遗传学计划，以及这些机制的消除调节如何有助于衰老和疾病。 SIRT6是Sirtuin酶家族中的染色质调节因子。小鼠的SIRT6缺乏导致与衰老，癌症和代谢相关的寿命和表型缩短。相反，小鼠中的SIRT6过表达可防止代谢疾病并延长寿命。研究SIRT6功能有望阐明健康衰老和寿命的基本机制。以前，我们表明SIRT6有选择地调节与表观遗传和基因调节功能相关的特定染色质标记。我们将SIRT6的染色质调节与影响衰老和癌症的关键核过程联系起来，包括维持端粒，DNA修复和与衰老相关的基因表达变化。在这里，我们关注SIRT6在染色质沉默机制中的新功能，这些机制在衰老中受管制。我们提出分子，基因组和功能研究，以研究SIRT6在重复性DNA元件上保持异染色质沉默中的作用，并询问沉默障碍与衰老相关的细胞功能障碍的影响。在AIM 1中，我们将研究SIRT6在centromeres的重复卫星DNA元件的异染色质沉默中的分子机制。在衰老和癌症的背景下，观察到上述异染色质的缺陷。我们将表征SIRT6在周围染色质上的生化活性，并在下游高阶染色质变化。我们的研究将提供有关癌细胞生物学的见解，SIRT6损失可能导致癌症的进展，并为人类体细胞细胞有助于，其中SIRT6可能会防止表观遗传可塑性的细胞感应或年龄依赖性下降。在AIM 2中，我们将表征SIRT6维持异染色质对细胞稳态的功能效应。我们将测试刺丁香异染色质缺陷触发异常有丝属的假设，染色体隔离缺陷和细胞感应，或促进细胞永生的致癌过程。我们还将在这些过程中检查SIRT6与其他SIRT酶之间的功能相互作用。这些研究应阐明如何将异染色质分解转化为细胞表型或有助于衰老和疾病的功能下降。在AIM 3中，我们将研究SIRT6在另一类重复的DNA元素中的作用，这些元素在衰老和癌症 - 内源性转载体可转移元件中受到管制。我们将询问这些元素沉默受损是否与可能影响细胞功能的基因组不稳定性或与衰老相关基因的异常转录有关。总之，这些研究应提供对衰老生物学中基本染色质机制的见解。