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Molecular Mechanisms of Mammalian SIRT6 Function

哺乳动物 SIRT6 功能的分子机制

基本信息

批准号：
9118549
负责人：
Katrin F Chua
金额：
$ 48.68万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118549
关键词：
Address Affect Aging Beryllium Biochemical 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 Genomics Goals Health Heterochromatin Homeostasis Human Human Genome Junk DNA Link Longevity Lysine Maintenance Malignant Neoplasms Mammalian Cell Metabolic Metabolic Diseases Mitosis Mitotic Modeling Molecular Mus Neurodegenerative Disorders Nuclear Oncogenic Pathogenesis Pathology Phenotype Process 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 functional genomics healthy aging human disease insight mammalian genome novel programs telomere tumor metabolism tumor progression

项目摘要

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 leads to cellular dysfunction associated with aging. In Aim 1, we will study the molecular mechanisms of SIRT6 in heterochromatin silencing of repetitive satellite DNA elements at centromeres. Defects in centromeric heterochromatin are observed in the contexts of both aging and cancer. We will characterize the biochemical activity of SIRT6 at centromeric chromatin, how this is regulated during mitosis, and how it affects 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 heterochromatin loss at centromeres triggers abnormal mitoses, chromosome segregation defects, and cellular senescence, and can 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 leads to genomic instability that can affect cellular function, or to aberrant transcription of aging- relatd 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。 SIRT6 是沉默调节蛋白家族中的一种染色质调节因子。小鼠 SIRT6 缺陷会导致寿命缩短以及与衰老、癌症和新陈代谢相关的表型。相反，SIRT6 在小鼠体内的过度表达可以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，我们表明 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。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，包括端粒维护、DNA 修复和衰老相关基因表达变化。在这里，我们重点关注 SIRT6 在衰老过程中失调的染色质沉默机制中的新功能。我们提出分子、基因组和功能研究来研究 SIRT6 在维持重复 DNA 元件异染色质沉默中的作用，并探究受损的沉默如何导致与衰老相关的细胞功能障碍。在目标 1 中，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都观察到着丝粒异染色质的缺陷。我们将描述 SIRT6 在着丝粒染色质上的生化活性、在有丝分裂过程中如何调节以及它如何影响高级染色质变化。我们的研究将为癌细胞生物学提供见解，其中 SIRT6 缺失可能会导致癌症进展；对于人类体细胞，SIRT6 可能会防止细胞衰老或表观遗传可塑性随年龄的下降。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。我们将测试以下假设：着丝粒异染色质丢失会引发异常有丝分裂、染色体分离缺陷和细胞衰老，并可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。这些研究应该阐明异染色质分解如何转化为导致衰老和疾病的细胞表型或功能下降。在目标 3 中，我们将研究 SIRT6 在另一类重复 DNA 元件（内源性逆转录转座元件）的异染色质维持中的作用，这些重复 DNA 元件在衰老和癌症中失调。我们将询问这些元件的沉默受损是否会导致影响细胞功能的基因组不稳定，或导致衰老相关基因的异常转录。总之，这些研究应该为衰老生物学中的基本染色质机制提供见解。