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: 10626849
• 负责人: Eugene V Shakirov
• 金额: $ 29.26万
• 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/10626849
• 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 H3.3; 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; Productivity; 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; candidate identification; chromatin modification; chromatin remodeling; enzyme activity; experimental study; gene conservation; 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; segregation; 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。大多数人类体细胞的端粒随着年龄的增长而缩短，并且 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、过早衰老和许多与年龄有关的疾病。虽然平均端粒 人类的长度显示出相当大的个体间差异，并且似乎受到强烈的影响 遗传控制，建立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，我们之前确定了几种候选植物 该物种自然端粒长度变异的基因。在本提案中，我们将利用 遗传、基因组、生物化学和表观遗传学方法探索其在端粒中的功能 长度控制和其他主要细胞过程，并获得进化视角 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TERT基因（编码端粒酶催化亚基）在植物中的作用 建立跨拟南芥基因型的天然端粒长度多态性。我们也会 使用强大的拟南芥基因组和转录组工具来识别和表征 TERT 反式调节剂并揭示端粒酶自然变异背后的新因素 多个拟南芥基因型的活性水平。通过一系列遗传 拟南芥端粒长度突变体的互补实验，目标​​ 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， 核糖体生物合成和染色质组装，并建立解剖蓝图 已识别基因的端粒与非端粒作用。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学方法来识别和验证其他 参与端粒长度控制的候选基因。总体而言，本研究的结果是 预计将显着增加我们对端粒遗传差异的理解 自然拟南芥种群的长度多态性。因为端粒的调节方式 高度保守，我们的数据还可以为分子基础提供新的见解 不同的衰老速度和与端粒长度相关的人类疾病的易感性 异常。