INVESTIGATING THE ASSOCIATION BETWEEN HYPOMETHYLATION OF TRANSPOSABLE ELEMENTS

研究转座元件低甲基化之间的关联

• 批准号: 8357854
• 负责人: Lucia Carbone
• 金额: $ 3.63万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357854
• 关键词: Acute Myelocytic Leukemia; Algorithms; Bioinformatics; Biological Models; Blast Cell; Chromosomal Rearrangement; Chromosomes; Custom; DNA Sequence; DNA Sequence Rearrangement; DNA Transposable Elements; Elements; Epigenetic Process; Funding; Genome; Genomics; Grant; Hylobates Genus; Libraries; Malignant - descriptor; Malignant Neoplasms; Maps; Measures; Methylation; Mutation; National Center for Research Resources; Normal Cell; Patients; Primates; Principal Investigator; Repetitive Sequence; Reporting; Research; Research Infrastructure; Resources; Source; Testing; United States National Institutes of Health; Variant; base; bisulfite; cost; next generation; structural genomics

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project will study the relationship between global hypomethylation, activation of Transposable Elements (TEs), and chromosomal rearrangements in cancer. TEs are DNA sequences that can move and insert randomly in the genome causing mutations, including large-scale chromosomal rearrangements. CpG methylation is the main mechanism to repress these elements and limit genomic damage. Both reduction of CpG-methylation (hypomethylation) and chromosomal rearrangements are common in cancer, although a causal relationship is unclear at this point. Using gibbons, which display an unusually high rate of evolutionary chromosome changes and therefore are an excellent model system for studying mechanisms of genomic structural variation, we have shown an association between undermethylated TEs (Alus) and chromosomal breakpoints. In this pilot, we will look for a similar association in cancer (somatic) chromosomal breakpoints and test different approaches based on next-generation sequencing on one Acute Myeloid Leukemia (AML) patient. We will generate short and long-range paired-end Illumina libraries from the blasts and normal cells of the patient in order to map the somatic rearrangements. Furthermore, we will measure CpG-methylation of TEs using whole-genome bisulfite sequencing. Custom algorithms and bioinformatics workflows will be generated to identify the epigenetic state of repetitive elements nearby breakpoints and study changes related to malignant transformation. As this grant was recently been funded, there is no progress to report at this point.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这个项目将研究癌症中整体低甲基化、转座元件(TES)的激活和染色体重排之间的关系。TES是一种DNA序列，可以在基因组中随机移动和插入，导致突变，包括大规模的染色体重排。CpG甲基化是抑制这些元件和限制基因组损伤的主要机制。CpG-甲基化减少(低甲基化)和染色体重排在癌症中都很常见，尽管目前因果关系尚不清楚。使用长臂猿，它显示出异常高的进化染色体变化率，因此是研究基因组结构变异机制的一个很好的模型系统，我们已经证明了甲基化不足的TES(ALU)和染色体断裂点之间的关联。在这项试验中，我们将在癌症(躯体)染色体断裂点中寻找类似的关联，并在一名急性髓系白血病(AML)患者身上测试基于下一代测序的不同方法。我们将从患者的原始细胞和正常细胞中生成短程和长程配对末端Illumina文库，以绘制体细胞重排的图谱。此外，我们将使用全基因组亚硫酸氢盐测序来测量TES的CpG甲基化。将生成定制算法和生物信息学工作流程，以识别断点附近重复元素的表观遗传状态，并研究与恶性转化相关的变化。由于这笔赠款是最近才资助的，目前没有进展可供报告。