Molecular Mechanisms of Mammalian SIRT6 Function

哺乳动物 SIRT6 功能的分子机制

• 批准号: 9901411
• 负责人: Katrin F Chua
• 金额: $ 37.4万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901411
• 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（由申请人提供）：我们的研究旨在了解染色质调控机制如何影响核和表观遗传程序，以及这些机制的失调如何导致衰老和疾病。 - 小鼠体内缺乏 SIRT6 会导致寿命缩短以及与衰老、癌症和代谢离线相关的表型，而小鼠体内 SIRT6 的过度表达可预防代谢疾病并延长寿命。因此，研究 SIRT6 功能有望阐明健康衰老和长寿的基本机制。此前，我们发现 SIRT6 选择性调节与表观遗传和基因调节功能相关的特定染色质标记，并将 SIRT6 的染色质调节与关键的核过程联系起来。 SIRT6 对衰老和癌症的影响，包括端粒维护、DNA 修复和衰老相关基因表达变化。在此，我们重点关注 SIRT6 在染色质中的新功能。我们提出分子、基因组和功能研究来研究 SIRT6 在维持重复 DNA 元件的异染色质沉默中的作用，并探讨受损的沉默如何与衰老相关的细胞功能障碍相关。我们将研究 SIRT6 在着丝粒重复卫星 DNA 元件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中心周异染色质缺陷。我们将表征 SIRT6 在中心周围染色质的生化活性，并研究下游高阶染色质的变化。我们的研究将为癌细胞生物学（其中 SIRT6 缺失可能导致癌症进展）和人类体细胞（其中 SIRT6 可能预防细胞生物学）提供见解。在目标 2 中，我们将描述 SIRT6 维持异染色质对细胞稳态的功能影响。中心周异染色质缺陷会引发异常有丝分裂、染色体分离缺陷和细胞衰老，或促进细胞永生化的致癌过程。我们还将研究这些过程中 SIRT6 和其他 SIRT 酶之间的功能相互作用。这些研究应阐明异染色质分解是如何转化的。在目标 3 中，我们将研究 SIRT6 在另一类重复性异染色质维持中的作用。在衰老和癌症中失调的 DNA 元件——内源性逆转录转座元件，我们将询问这些元件的沉默受损是否与影响细胞功能的基因组不稳定性有关，或者与衰老相关基因的异常转录有关。对衰老生物学中基本染色质机制的见解。