The role of RNA in centromere chromatin

RNA在着丝粒染色质中的作用

• 批准号: 8208282
• 负责人: Jonathan Isaiah Gent
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208282
• 关键词: Aneuploidy; Area; Base Sequence; Binding; Biology; Cell division; Cells; Cellular Structures; Centromere; Chromatin; Chromosomes; Complement; Complex; DNA Sequence; Defect; Detection; Dicentric chromosome; Environment; Epigenetic Process; Gene Expression Profile; Generations; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Health; Human; Investigation; Kinetochores; Knowledge; Lead; Maize; Maps; Methods; Microtubules; Modern Medicine; Molecular; Organism; Plant Model; Plants; Play; Population; Proteins; RNA; RNA Binding; RNA Sequences; RNA library; Reagent; Regulation; Reporting; Research; Resources; Reverse Transcriptase Polymerase Chain Reaction; Role; Site; Specific qualifier value; Specificity; Surveys; System; Testing; Work; base; design; deviant; expectation; experience; gene therapy; high throughput screening; human disease; mutant; novel; public health relevance; research study; transmission process

DESCRIPTION (provided by applicant): At a superficial level, the concept of a centromere is straightforward: the part of a chromosome that provides a favorable chromatin environment for kinetochore assembly and microtubule attachments during cell division. At a molecular level, however, the concept of a centromere is quite murky and involves a complex interaction between genetic and epigenetic factors. While in many organisms centromeres have been mapped to specific genetic loci and many of their protein components identified, fundamental questions about what regulates centromere identity and function remain unanswered. Recent evidence suggests that RNA plays an important role in centromere chromatin. The central goal of this proposed research is to understand the contribution of chromatin-associated RNA to centromere regulation and function. We have chosen to use the model plant species maize for the proposed experiments because of its unique advantages in studying centromere biology and because of the availability of resources and reagents tailored to our needs. In particular, maize is unrivaled for cytological analysis, provides multiple examples of epigenetic centromere deviants, and has the distinction of being the first organism in which chromatin-bound centromere RNA was detected. The following specific aims will make use of a number of complementary experimental approaches, but will rely substantially on our strengths and experience with characterization of diverse RNA populations through deep sequencing. 1) Survey and characterization of the centromere RNAome, 2) Delineation of the rules-of-engagement for RNA in centromere chromatin, and 3) Identification of novel centromere regulatory factors. We anticipate that this work will lead towards progress in several important areas of research connected to human health including causes of aneuploidy and relation to human disease, rational design of minichromosomes for gene therapy, and understanding of complex heritable epigenetic phenomena (based on the knowledge gained from the exemplary and easily tractable system provided by centromeres). PUBLIC HEALTH RELEVANCE: Modern medicine has greatly benefitted from scientific investigation into the molecular details of the cell and the genes that encode each component. What we hope to gain through our proposed research is a clearer understanding of the centromere, a fundamental cellular structure that is essential for accurate and reliable transmission of genes from one generation to the next. )

描述（由申请人提供）：从表面上讲，丝粒的概念很简单：染色体的一部分，该染色体为动物学组装提供了有利的染色质环境，并在细胞分裂过程中提供了微管附件。然而，在分子水平上，丝粒的概念非常模糊，涉及遗传因素和表观遗传因素之间的复杂相互作用。尽管在许多生物体中，Centromeres已被映射到特定的遗传基因座及其许多蛋白质成分，但有关调节Centromere身份和功能的基本问题仍未得到解答。最近的证据表明，RNA在丝粒染色质中起重要作用。这项拟议的研究的核心目标是了解与染色质相关的RNA对丝粒调节和功能的贡献。我们之所以选择将模型植物玉米用于拟议的实验，是因为它在研究Centromere生物学方面具有独特的优势，并且由于根据我们的需求量身定制的资源和试剂的可用性。特别是，玉米是无与伦比的细胞学分析，提供了表观遗传性丝粒变形的多个例子，并且具有第一个检测到染色质的丝粒RNA的区别。以下特定目标将利用多种互补的实验方法，但在很大程度上依靠我们的优势和经验，并通过深层测序来表征不同的RNA种群。 1）Centromere RNAome的调查和表征，2）描述Centromere染色质中RNA的参与规则，以及3）鉴定新的中心粒调节因素。我们预计，这项工作将导致与人类健康相关的几个重要研究领域的进步，包括非整倍性和与人类疾病关系的原因，用于基因治疗的微小浓度小体的合理设计以及对复杂可遗传的表观遗传现象的理解（基于Centromeres提供的典范和易于冻结的系统所获得的知识）。 公共卫生相关性：现代医学从科学研究中对细胞的分子细节和编码每个组件的基因的分子细节受益匪浅。我们希望通过拟议的研究获得的是对Centromere的更清晰的了解，Centromere是一种基本的细胞结构，对于从一代到另一代的基因准确而可靠的传播至关重要。 ）