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: 10446527
• 负责人: Eugene V Shakirov
• 金额: $ 31.35万
• 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 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446527
• 关键词: ATRX gene; Address; Age; Aging; Alleles; Arabidopsis; Architecture; Biochemical; Biogenesis; Biological; Biological Assay; Biological Markers; Biology; Candidate Disease Gene; Cell Proliferation; Cell division; Cell physiology; Cellular biology; Chimeric Proteins; Chromatin Modeling; Chromosomes; Collection; Complement; Complex; DNA; DNA Methylation; Data; Deposition; Disease; Epigenetic Process; Eukaryota; Eukaryotic Cell; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genome; Genomic approach; Genomics; Genotype; Goals; Histone H3; Histones; Holoenzymes; Homeostasis; Human; Inbreeding; Individual; Lead; Length; Longevity; Maintenance; Malignant Neoplasms; Maps; Modeling; Molecular; Mouse-ear Cress; Mutation; Nature; Orthologous Gene; Pathway interactions; Phenotype; Plant Model; Plants; Play; Population; Predisposition; Premature aging syndrome; Proteins; Quantitative Trait Loci; Recombinants; Regulation; Resources; Ribosomes; Role; Series; Somatic Cell; TERT gene; Telomerase; Telomere Length Maintenance; Telomere Maintenance; Telomere Maintenance Gene; Telomere Shortening; Transgenic Organisms; Variant; Yeasts; age related; base; chromatin modification; chromatin remodeling; enzyme activity; experimental study; gene discovery; gene function; gene network; genome wide association study; genome wide screen; genome-wide; human disease; in vivo; inhibitor; innovation; insight; inter-individual variation; multidisciplinary; mutant; novel; pleiotropism; stem cells; telomere; tool; 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 somatic 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. Using the model plant Arabidopsis thaliana, we previously identified several candidate genes underlying natural telomere length variation in this species. In this proposal, we will utilize genetic, genomic, biochemical and epigenetic approaches to explore their functions in telomere length control and other major cellular processes, and to gain an evolutionary perspective on functional gene pleiotropy. In Aim 1, we will explore several hypotheses for direct and indirect roles of Arabidopsis TERT gene, which encodes the catalytic subunit of telomerase, in establishing natural telomere length polymorphism across Arabidopsis genotypes. We will also employ powerful Arabidopsis genomic and transcriptomic tools to identify and characterize TERT trans-regulators and uncover novel factors underlying natural variation in telomerase enzyme activity levels across multiple Arabidopsis genotypes. Through a series of genetic complementation experiments with Arabidopsis telomere length mutants, experiments in Aim 2 will address the nature and extent of functional redundancies between telomere biology, ribosome biogenesis and chromatin assembly, and establish the blueprint for dissecting telomeric versus non-telomeric roles of identified genes. Additionally, in Aim 2 we will utilize several innovative genomic and epigenetic approaches to identify and validate additional candidate genes involved in telomere length control. Overall, the results of this study are expected to significantly increase our 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 human diseases associated with telomere length abnormalities.

项目摘要 端粒是进化上保守的蛋白质-DNA复合物，位于端粒的物理末端。 线性真核染色体。在大多数人体细胞中，端粒随着年龄的增长而缩短， 它们的初始长度预先决定了细胞的寿命。端粒维持基因突变 导致癌症、过早衰老和一些与年龄有关的疾病。而平均端粒 人类的长度显示出相当大的个体间差异， 遗传控制，确定端粒长度设定点的因素的确切性质仍然存在， 难以捉摸。使用模式植物拟南芥，我们先前确定了几个候选 基因的自然端粒长度变化在这个物种。在本提案中，我们将利用 通过遗传学、基因组学、生物化学和表观遗传学的方法来研究端粒的功能 长度控制和其他主要的细胞过程，并获得进化的观点， 功能基因多效性在目标1中，我们将探讨直接和间接的几个假设， 拟南芥端粒酶催化亚基基因在端粒酶活性调节中的作用 在拟南芥基因型中建立天然端粒长度多态性。我们还将 使用强大的拟南芥基因组和转录组学工具来鉴定和表征TERT 反式调节子，并揭示端粒酶自然变异的新因素 在多种拟南芥基因型之间的活性水平。通过一系列的基因 拟南芥端粒长度突变体的互补实验，Aim 2中的实验 将解决端粒生物学之间功能冗余的性质和程度， 核糖体生物发生和染色质组装，并建立解剖蓝图 端粒与非端粒的角色的鉴定基因。此外，在目标2中，我们将利用 几种创新的基因组和表观遗传方法，以确定和验证其他 参与端粒长度控制的候选基因。总的来说，这项研究的结果是 有望大大增加我们对端粒遗传差异的理解 长度多态性在自然拟南芥种群。因为端粒调节的模式 是高度保守的，我们的数据也可能提供新的见解的分子基础， 与端粒长度相关的不同衰老率和人类疾病易感性 异常