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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要端粒是进化上保守的蛋白质-DNA 复合物，位于染色体的物理末端。线性真核染色体。大多数人类细胞的端粒随着年龄的增长而缩短，初始长度预先决定细胞的寿命。端粒维持基因突变导致癌症、过早衰老和许多与年龄有关的疾病。虽然平均端粒长度为人类表现出相当大的个体间差异，并且似乎受到强大的遗传影响控制，建立端粒长度设定点的因素的确切性质仍然难以捉摸。在我们的使用模式植物拟南芥的初步结果，我们确定了一个主要效应QTL 重组近交群体可以解释 48% 的端粒长度变异并绘制该图候选基因 NOP2A 的 QTL。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展的预后标志物。在这个提案中，我们将利用遗传、基因组、生物化学和表观遗传学方法来破译该机制 AtNOP2A 功能，并揭示参与的其他遗传和表观遗传因素端粒长度控制。目标1，通过一系列定量转基因拯救实验我们将确定因果 SNP 并探索 NOP2A 影响端粒的机制长度。我们还将利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因子。在目标 2 中，我们将对 1,001 个拟南芥基因型进行 GWAS 并在双亲本中精细定位额外的 QTL 拟南芥 RIL 群体鉴定影响端粒长度的新多态性。我们将然后进行一系列的敲除和转基因拯救实验以实现功能性表征候选基因并验证它们在端粒生物学中的作用。在目标 3 中，我们将利用具有几乎相同 DNA 的独特拟南芥表观遗传重组近交群体序列，但甲基化和基因表达谱可变，以精细映射之前的两个鉴定了控制端粒长度的大效应表观 QTL，并分析了表观遗传的遗传性变异直接影响端粒长度。总体而言，本研究的结果预计显着增加对端粒长度遗传差异的理解自然拟南芥种群的多态性。因为端粒的调控方式是高度保守，我们的数据还可以为不同的分子基础提供新的见解人类的衰老速度和与端粒异常相关的疾病的易感性。