Linking evolution to aging through DNA methylation and CpG density by examining twelve mammalian species

通过检查 12 种哺乳动物，通过 DNA 甲基化和 CpG 密度将进化与衰老联系起来

• 批准号: 10597245
• 负责人: Christopher Faulk
• 金额: $ 19.33万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597245
• 关键词: Address; Adolescent; Adult; African Green Monkey; Age; Aging; Animals; Area; Biological; Biological Clocks; Biology; Buffers; Callithrix; Cells; Cessation of life; Chronology; CpG Islands; CpG dinucleotide; DNA Methylation; Data; Disease; Elderly; Epigenetic Process; Evolution; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Genomics; Health; Human; Individual; Intervention; Laboratories; Lemurs; Life; Link; Longevity; Macaca mulatta; Mammals; Methylation; Mitochondria; Mole Rats; Molecular; Mus; Mutation; Natural Selections; Nuclear; Organism; Pan Genus; Papio; Phenotype; Population; Primates; Process; Promoter Regions; Rattus; Recording of previous events; Regulation; Reporting; Rodent; Role; Shapes; Signal Transduction; Site; Squirrel; Surveys; Tail; Testing; Time; Validation; Variant; age related; bisulfite sequencing; cohort; comparative genomics; cost; density; design; epigenome; epigenomics; gene repression; genetic testing; genome wide methylation; genome-wide; innovation; insight; mammalian genome; novel; preservation; promoter; public health relevance; senescence; sex

Project Summary As organisms age, gene regulation becomes increasingly unstable along with changes in the epigenome. Within the genome, a principle epigenetic mark, DNA methylation, occurs at CpG dinucleotides generally causing gene repression. Thus, CpG sites act as genetic control switches depending on their methylation status. As we age, CpG sites gain methylation at gene promoters and drifting methylation levels cause variation between cells and individuals. Methylated CpG sites are also highly mutagenic, so over evolutionary time there has been a depletion of CpG dinucleotides in mammalian species. Together these facts raise a fundamental question. Is the aging process linked to the evolution of a species by the selection of CpG sites at specific genes? Across one hundred thirty-one mammal species, many of them separated by tens of millions of years of evolutionary history, we revealed that in about 1000 genes, CpG density in promoters was positively correlated with species’ lifespans. These genes showed increased CpG density concomitant with increased lifespan and are indicative of an underlying biological signal, one that merits further exploration in order to elucidate insights into the genetic basis of aging. Our main hypothesis is that increased CpG density buffers the impacts of increased methylation during aging. This proposal aims to address two fundamental questions in biology: 1) Have these genes become targets for evolution, increasing in CpG density in long-lived species to maintain epigenetic integrity and preserve gene expression during aging? 2) Does the epigenome drift less in these genes, resulting in more stable gene expression over time in long-lived species? To address these questions, we will examine the epigenomes of individuals from twelve different mammalian species (8 primates, 4 rodents) in three age cohorts (juveniles, sexually mature adults, elder individuals). Using genome- wide reduced-representation bisulfite sequencing, we will compare gene promoter DNA methylation over time and across species. Aim 1 will explore how natural selection impacts DNA methylation differently in long-lived vs. short lived species. Aim 2 will examine how genes become unstable over time and how natural selection selects against that instability. Through these studies we hope to uncover whether epigenetic marks at specific genes are important drivers of aging, therefore providing interventional targets and a molecular mechanism of evolutionary innovation for long lifespan. Currently, this idea is supported by computational comparative genomics, yet does not have a clear molecular explanation. Laboratory validation of the link between the aging epigenome and the evolution of CpG density with lifespan could have broad impact on our understanding of how we age.

项目摘要 随着生物体的年龄，随着表观基因组的变化，基因调节变得越来越不稳定。 在基因组中，通常在CpG二核苷酸上出现一个原理表观遗传标记，DNA甲基化 引起基因表达。这是CPG位点作为遗传控制开关的起作用，具体取决于其甲基化 地位。随着年龄的增长，CpG位点在基因启动子处获得甲基化，驱动甲基化水平会导致 细胞与个体之间的变化。甲基化的CpG位点也高度诱变，因此超过进化 哺乳动物物种中CpG二核苷酸的耗尽。这些事实共同提出了 基本问题。是通过选择在 特定基因？在一百三十一种哺乳动物中，其中许多被隔开了数千万 多年的进化史，我们透露，在大约1000个基因中，启动子中的CpG密度是积极的 与物种的寿命相关。这些基因显示CpG密度增加，随着增加 寿命，表明存在潜在的生物学信号，该信号值得进一步探索以便 阐明对衰老遗传基础的见解。我们的主要假设是增加CpG密度缓冲液 衰老过程中甲基化增加的影响。该建议旨在解决两个基本问题 在生物学中：1）使这些基因成为进化的靶标，在长寿物种中的CpG密度增加 保持表观遗传完整性并保留衰老期间的基因表达？ 2）表观基因组漂移较少 在这些基因中，在长寿物种中会随着时间的流逝而产生更稳定的基因表达？解决这些 问题，我们将研究来自十二种不同哺乳动物的个体的表观观察者（8个 灵长类动物，4个啮齿动物）三个年龄群（少年，性成熟的成年人，老年人）。使用基因组 - 较大的降低占代表性的亚硫酸盐测序，我们将随着时间的推移比较基因启动子DNA甲基化 和跨物种。 AIM 1将探索自然选择如何在长寿的情况下影响DNA甲基化 vs.短生物。 AIM 2将检查基因如何随着时间的流逝而变得不稳定以及如何自然选择 选择这种不稳定。通过这些研究，我们希望发现表观遗传标记是否在特定上 基因是衰老的重要驱动因素，因此提供介入靶标和分子机制 长期寿命的进化创新。目前，计算比较支持了这个想法 基因组学，但没有明确的分子解释。实验室验证老化之间的联系 表观基因组和CpG密度随寿命的发展可能对我们对我们对的理解有广泛的影响 我们的年龄。