Roles for Global Chromatin Structure in C. elegans Longevity

整体染色质结构在秀丽隐杆线虫长寿中的作用

• 批准号: 7915625
• 负责人: Siu Sylvia Lee
• 金额: $ 16.3万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915625
• 关键词: Affect; Age; Aging; Area; Biological Models; Biology of Aging; Caenorhabditis elegans; Cell division; Cells; Characteristics; Chromatin; Chromatin Structure; Coupled; Cultured Cells; DNA; DNA Methylation; DNA Sequence; Data; Disease; Enzymes; Epigenetic Process; Functional RNA; Future; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Histones; Human; Inherited; Lead; Life; Link; Location; Longevity; Maintenance; Mammals; Messenger RNA; Methods; Molecular; Molecular Profiling; Monitor; Monozygotic Twinning; Monozygotic twins; Nematoda; Organism; Pathway interactions; Pattern; Play; Polymerase; Post-Translational Protein Processing; Proteins; RNA Polymerase II; RNA Splicing; Research; Reverse Transcription; Role; Soil; Specific qualifier value; Techniques; Testing; Time; Tissues; Transcript; Yeasts; age related; chromatin immunoprecipitation; fly; healthy aging; histone modification; improved; insight; mRNA Expression; molecular marker; mutant; novel; public health relevance; therapeutic development; tool

DESCRIPTION (provided by applicant): Recent research has revealed many evolutionarily conserved genetic pathways important for longevity. In contrast, relatively little is known about the role of epigenetic changes in organismal aging. Epigenetic changes, such as altered levels or patterns of DNA methylation and post-translational histone modifications, have been observed in a variety of aging mammalian tissues and in aging human monozygotic twins. In yeast, worms, and flies, several histone modifying enzymes have been shown to play critical roles in determining longevity. Thus, emerging evidence points to a mechanistic link between chromatin structure and longevity. The goal of this proposal is to explore how global chromatin structure changes with aging in C. elegans. Because DNA methylation is nearly undetectable in C. elegans, post-translational modification of histones is likely the major regulatory mechanism of chromatin state in C. elegans. How the global chromatin state changes with age in C. elegans is completely unknown. In Aim 1, we propose to determine the genomic distribution and abundance of several major histone modifications in C. elegans of different age using the ChIP-seq technique. In Aim 2, we propose to comprehensively examine the transcriptional profiles of C. elegans at different age using the RNA-seq technique. Although the transcriptional profiles of C. elegans through aging have previously been examined using microarray studies, microarray studies have multiple limitations and the RNA-seq technique is generally considered to provide a much more comprehensive view of gene expression profiles. We plan to compare the ChIP-seq and the RNA-seq results to identify, with high confidence, the genes that show age-dependent changes, even for genes that are expressed at low levels and those that only show subtle expression changes. Comparing the ChIP-seq and the RNA-seq results will also reveal age-dependent changes in alternatively spliced transcripts, as well as novel transcripts that have not been previously annotated, including non- coding RNAs. These changes are likely not revealed previously due to the limitations of previous gene expression studies. Comparing the ChIP-seq and RNA-seq data will also provide insights into the chromatin state that help specify age-dependent mRNA expression changes. Some of the age-dependent histone modification and mRNA expression changes may represent valuable molecular markers of aging. Importantly, some of these changes may point to regulatory factors that contribute to longevity determination. Our proposed research will be the first to globally profile how chromatin state is impacted as C. elegans age. Considering the high degree of conservation between the genetic pathways that modulate longevity in C. elegans and mammals, we anticipate that some of the epigenetic mechanisms that impact C. elegans longevity will also be conserved in mammals. PUBLIC HEALTH RELEVANCE: This application proposes to investigate how aging is impacted by certain special features of the genome that are stably inherited through multiple rounds of cell division, but do not involve changes in the DNA sequence. These epigenetic features often involve specific decorations of the DNA or the proteins that help compact DNA, and their proper maintenance is critically important for cells and organisms to maintain certain characteristics. To date, very little is known about how these epigenetic features affect aging and age-dependent diseases, and our research proposes to use two different comprehensive approaches to examine how changes in these features affect longevity in the powerful model system soil nematode. Our proposed research may lead to future therapeutic development that aims to improve healthy aging and alleviate age-dependent diseases.

描述（由申请人提供）：最近的研究揭示了许多进化上保守的遗传途径对长寿很重要。相比之下，人们对表观遗传变化在机体衰老中的作用知之甚少。表观遗传变化，如DNA甲基化和翻译后组蛋白修饰水平或模式的改变，已经在各种衰老的哺乳动物组织和衰老的人类同卵双胞胎中观察到。在酵母、蠕虫和苍蝇中，几种组蛋白修饰酶已被证明在决定寿命方面起着关键作用。因此，新出现的证据指出了染色质结构和寿命之间的机制联系。本提案的目的是探索线虫的整体染色质结构如何随着衰老而变化。由于在秀丽隐杆线虫中几乎检测不到DNA甲基化，因此组蛋白的翻译后修饰可能是秀丽隐杆线虫染色质状态的主要调控机制。秀丽隐杆线虫的整体染色质状态如何随年龄变化是完全未知的。在Aim 1中，我们建议使用ChIP-seq技术确定不同年龄秀丽隐杆线虫中几种主要组蛋白修饰的基因组分布和丰度。在Aim 2中，我们建议使用RNA-seq技术全面检查不同年龄秀丽隐杆线虫的转录谱。虽然以前已经使用微阵列研究了秀丽隐杆线虫在衰老过程中的转录谱，但微阵列研究有多种局限性，RNA-seq技术通常被认为可以提供更全面的基因表达谱视图。我们计划比较ChIP-seq和RNA-seq结果，以高可信度识别显示年龄依赖性变化的基因，即使是低水平表达的基因和仅显示细微表达变化的基因。比较ChIP-seq和RNA-seq结果还将揭示选择性剪接转录物的年龄依赖性变化，以及以前未被注释的新转录物，包括非编码rna。由于先前基因表达研究的局限性，这些变化可能没有被揭示出来。比较ChIP-seq和RNA-seq数据也将提供对染色质状态的见解，有助于确定年龄依赖性mRNA表达的变化。一些年龄依赖性组蛋白修饰和mRNA表达变化可能是衰老的有价值的分子标记。重要的是，其中一些变化可能指向有助于决定寿命的调节因素。我们提出的研究将是第一个全球概况染色质状态如何影响秀丽隐杆线虫的年龄。考虑到调节秀丽隐杆线虫和哺乳动物寿命的遗传途径之间的高度保守性，我们预计影响秀丽隐杆线虫寿命的一些表观遗传机制也将在哺乳动物中保守。公共卫生相关性：本应用旨在研究基因组的某些特殊特征如何影响衰老，这些特征通过多轮细胞分裂稳定地遗传，但不涉及DNA序列的变化。这些表观遗传特征通常涉及DNA的特定修饰或帮助DNA紧密化的蛋白质，它们的适当维护对细胞和生物体保持某些特征至关重要。迄今为止，我们对这些表观遗传特征如何影响衰老和年龄依赖性疾病知之甚少，我们的研究建议使用两种不同的综合方法来研究这些特征的变化如何影响强大模型系统土壤线虫的寿命。我们提出的研究可能会导致未来的治疗发展，旨在改善健康老龄化和减轻年龄依赖性疾病。