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：
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
项目类别：
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

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 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）：我们的研究试图染色质机制影响核能核和杂志S，以及这些机制对衰老和疾病的失调如何导致小鼠的缺乏症。代谢可预防代谢疾病和研究SIRT 6的功能，有望阐明衰老和寿命的机制。衰老和癌症，DNA修复相关的基因表达变化，以及研究SIRT6在重复性DNA元素中保持沉默的作用在衰老和癌症的情况下，观察到周围的异染色质的DNA元素。 AIM 2中的体细胞衰老或年龄依赖性下降，我们将表征SIRT6杂色素维持对细胞ULAR稳态的功能效应。细胞不变，我们还将在这些研究中研究SIRT6和其他SIRT的疾病。在衰老和癌症的逆转录元素中，我们将询问这些元素的沉默是否与cel lular功能或衰老相关的异常转录相关的基因组界面。