Genetic and epigenetic architecture of natural telomere length variation

自然端粒长度变异的遗传和表观遗传结构

• 批准号: 9923707
• 负责人: Eugene V Shakirov
• 金额: $ 27.27万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923707
• 关键词: Affect; Age; Aging; Alleles; Arabidopsis; Architecture; Biochemical; Biological; Biological Assay; Biological Markers; Biology; Candidate Disease Gene; Cell Cycle; Cell division; Cells; Chromosomes; Collection; Complex; DNA; DNA Methylation; DNA Sequence; Data; Development; Disease; Epigenetic Process; Eukaryota; Expression Profiling; Foundations; Frequencies; Funding; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Epistasis; Genetic Polymorphism; Genetic Variation; Genome; Genomic Segment; Genomics; Genotype; Goals; Heritability; Homeostasis; Human; Inbreeding; Individual; Knock-out; Lead; Length; Link; Longevity; Maintenance; Malignant Neoplasms; Maps; Methylation; Modeling; Molecular; Mouse-ear Cress; Mutation; Nature; Orthologous Gene; Parents; Pathway interactions; Phenotype; Plant Model; Plants; Population; Predisposition; Premature aging syndrome; Prognostic Marker; Proteins; QTL Genes; Quantitative Genetics; Quantitative Trait Loci; RNA methylation; Recombinants; Regulation; Regulator Genes; Resources; Role; Series; Somatic Cell; Telomere Length Maintenance; Telomere Maintenance Gene; Telomere Shortening; Testing; Transcript; Transgenic Organisms; Tumor Markers; Variant; Yeasts; age related; base; cancer cell; comparative; epigenetic variation; experimental study; genetic architecture; genome wide association study; genomic locus; human disease; insight; inter-individual variation; multidisciplinary; mutant; novel; stem cells; telomere; tool; transcriptome sequencing; transcriptomics; tumorigenesis

Project Summary Telomeres are evolutionarily conserved protein-DNA complexes at the physical ends of linear eukaryotic chromosomes. Telomeres shorten with age in most human cells, and their initial length pre-determines cellular lifespan. Mutations in telomere maintenance genes lead to cancer, premature aging and a number of age-related disorders. While mean telomere length in humans shows considerable inter-individual variation and appears to be under strong genetic control, the exact nature of factors establishing telomere length set point remains elusive. In our preliminary results using the model plant Arabidopsis thaliana we identify a major effect QTL in a recombinant inbred population that explains 48% of telomere length variation and map this QTL to a candidate gene, NOP2A. Notably, expression of the human NOP2 ortholog is linked to tumorigenesis and serves as a prognostic marker of tumor development. In this proposal, we will utilize genetic, genomic, biochemical and epigenetic approaches to decipher the mechanism of AtNOP2A function, and to uncover additional genetic and epigenetic factors involved in telomere length control. In Aim 1, through a series of quantitative transgenic rescue experiments we will identify the causal SNP and explore the mechanism by which NOP2A impacts telomere length. We will also employ powerful Arabidopsis genetic, genomic and transcriptomic tools to identify and characterize NOP2A-dependent genes and trans-regulators. In Aim 2, we will perform GWAS in 1,001 Arabidopsis genotypes and fine-map additional QTL in a bi-parental Arabidopsis RIL population to identify novel polymorphisms that affect telomere length. We will then perform a series of knock-out and transgenic rescue experiments to functionally characterize candidate genes and validate their role in telomere biology. In Aim 3, we will utilize a unique A. thaliana epigenetic recombinant inbred population with almost identical DNA sequences, but variable methylation and gene expression profiles, to fine-map two previously identified large-effect epi-QTL governing telomere length, and analyze how heritable epigenetic variation directly affects telomere length. Overall, the results of this study are expected to significantly increase understanding of genetic differences underlying telomere length polymorphism in natural Arabidopsis populations. Because modes of telomere regulation are highly conserved, our data may also provide novel insight into the molecular basis for different rates of aging and predisposition to diseases associated with telomere abnormalities in humans.

项目摘要 端粒是在进化上保守的蛋白-DNA复合物 线性真核染色体。大多数人类细胞及其 初始长度预先确定的细胞寿命。端粒维持基因的突变导致 癌症，过早衰老和许多与年龄有关的疾病。而平均端粒长度为 人类表现出很大的个体变化，似乎处于强遗传之下 控制，建立端粒长度设定点的因素的确切性质仍然难以捉摸。在我们的 使用模型植物拟南芥的初步结果，我们确定了在 一个重组近交的人群，解释了48％的端粒长度变化，并绘制了这一点 QTL候选基因NOP2A。值得注意的是，人类NOP2直系同源物的表达与 肿瘤发生，并作为肿瘤发育的预后标志。在这个建议中，我们 将利用遗传，基因组，生化和表观遗传学方法来破译机制 ATNOP2A功能，并发现涉及的其他遗传和表观遗传因素 端粒长度控制。在AIM 1中，通过一系列定量转基因救援实验 我们将确定因果SNP并探索NOP2A影响端粒的机制 长度。我们还将使用强大的拟南芥遗传，基因组和转录组工具来 识别和表征NOP2A依赖性基因和反式调节剂。在AIM 2中，我们将 在1,001个拟南芥基因型中执行GWAS，并在双方 拟南芥种群鉴定影响端粒长度的新型多态性。我们将 然后执行一系列的敲除和转基因救援实验 表征候选基因并验证其在端粒生物学中的作用。在AIM 3中，我们将使用 独特的A. thaliana表观遗传重组植物种群几乎相同的DNA 以前 确定了端粒长度的大效应Epi-QTL，并分析了遗传遗传学 变异直接影响端粒长度。总体而言，这项研究的结果有望 显着增加对端粒长度基础遗传差异的理解 天然拟南芥种群中的多态性。因为端粒调节模式是 高度保守，我们的数据还可以为不同的分子基础提供新的见解 与人类端粒异常相关的疾病的衰老率和倾向。