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
基本信息
- 批准号:10597245
- 负责人:
- 金额:$ 19.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdolescentAdultAfrican Green MonkeyAgeAgingAnimalsAreaBiologicalBiological ClocksBiologyBuffersCallithrixCellsCessation of lifeChronologyCpG IslandsCpG dinucleotideDNA MethylationDataDiseaseElderlyEpigenetic ProcessEvolutionGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGenomeGenomicsHealthHumanIndividualInterventionLaboratoriesLemursLifeLinkLongevityMacaca mulattaMammalsMethylationMitochondriaMole RatsMolecularMusMutationNatural SelectionsNuclearOrganismPan GenusPapioPhenotypePopulationPrimatesProcessPromoter RegionsRattusRecording of previous eventsRegulationReportingRodentRoleShapesSignal TransductionSiteSquirrelSurveysTailTestingTimeValidationVariantage relatedbisulfite sequencingcohortcomparative genomicscostdensitydesignepigenomeepigenomicsgene repressiongenetic testinggenome wide methylationgenome-wideinnovationinsightmammalian genomenovelpreservationpromoterpublic health relevancesenescencesex
项目摘要
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.
项目概要
随着生物体年龄的增长,基因调控随着表观基因组的变化而变得越来越不稳定。
在基因组内,主要的表观遗传标记 DNA 甲基化通常发生在 CpG 二核苷酸处
因此,CpG 位点根据其甲基化程度充当遗传控制开关。
随着年龄的增长,CpG 位点在基因启动子处获得甲基化,并导致甲基化水平漂移。
细胞和个体之间的甲基化 CpG 位点也具有高度诱变性,因此过度进化。
哺乳动物中的 CpG 二核苷酸已经耗尽,这些事实共同提出了一个问题。
衰老过程是否通过 CpG 位点的选择与物种的进化相关。
跨越一百三十一个哺乳动物物种,其中许多物种相隔数千万个特定基因?
经过多年的进化史,我们发现在大约1000个基因中,启动子中的CpG密度呈正向分布
这些基因显示出随着 CpG 密度的增加而增加。
寿命,并表明了一种潜在的生物信号,值得进一步探索,以便
我们的主要假设是 CpG 密度缓冲增加。
该提案旨在解决衰老过程中甲基化增加的影响。
生物学:1)这些基因是否成为进化的目标,增加长寿物种的 CpG 密度
在衰老过程中保持表观遗传完整性并保留基因表达? 2)表观基因组漂移是否较少?
随着时间的推移,长寿物种的基因表达会更加稳定?
问题,我们将检查来自十二个不同哺乳动物物种的个体的表观基因组(8
灵长类动物,4 种啮齿类动物),分为三个年龄组(青少年、性成熟的成年人、老年个体)。
广泛简化代表性亚硫酸氢盐测序,我们将比较基因启动子 DNA 甲基化随时间的变化
目标 1 将探索自然选择如何对长寿的 DNA 甲基化产生不同的影响。
目标 2 将研究基因如何随着时间的推移变得不稳定以及自然选择如何。
通过这些研究,我们希望揭示表观遗传标记是否存在于特定的位置。
基因是衰老的重要驱动因素,因此提供了干预靶点和分子机制
目前,这一想法得到了计算比较的支持。
基因组学尚未对衰老之间的联系做出明确的分子解释。
表观基因组和 CpG 密度随寿命的演变可能会对我们的理解产生广泛的影响
我们几岁了?
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christopher Faulk其他文献
Christopher Faulk的其他文献
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{{ truncateString('Christopher Faulk', 18)}}的其他基金
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:
10371683 - 财政年份:2022
- 资助金额:
$ 19.33万 - 项目类别:
The Environment and Epigenome: Interplay of Toxicants and Transposons in Mammals
环境和表观基因组:哺乳动物中毒素和转座子的相互作用
- 批准号:
9091753 - 财政年份:2015
- 资助金额:
$ 19.33万 - 项目类别:
The Environment and Epigenome: Interplay of Toxicants and Transposons in Mammals
环境和表观基因组:哺乳动物中毒素和转座子的相互作用
- 批准号:
8423106 - 财政年份:2013
- 资助金额:
$ 19.33万 - 项目类别:
The Environment and Epigenome: Interplay of Toxicants and Transposons in Mammals
环境和表观基因组:哺乳动物中毒素和转座子的相互作用
- 批准号:
8725664 - 财政年份:2013
- 资助金额:
$ 19.33万 - 项目类别:
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