Integrative Analysis of DNA Replication Timing in Cancer

癌症中 DNA 复制时间的综合分析

• 批准号: 10523135
• 负责人: Michael B Heskett
• 金额: $ 8.39万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523135
• 关键词: 3-Dimensional; Affect; Alleles; Back; Behavior; Bioinformatics; Biological Assay; Biological Models; Biology; Biometry; Cancer Diagnostics; Cancer Model; Cell Line; Cell model; Cells; Chromatin; Chromatin Structure; Chromosomal Loss; Chromosomal Rearrangement; Chromosomal Stability; Chromosome 15; Chromosome 6; Chromosome Condensation; Chromosome Deletion; Chromosome Structures; Chromosome abnormality; Chromosomes; Clone Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Communities; DNA Replication Timing; DNA analysis; DNA biosynthesis; DNA replication fork; Data Set; Development; Elements; Event; Family; Fluorescent in Situ Hybridization; Future; Gene Expression; Genes; Genetic Nondisjunction; Genetic Transcription; Genome; Genome Stability; Genomic Instability; Genomics; Haplotypes; Health; Human; Human Characteristics; Human Chromosomes; Human Cloning; In Vitro; Institutes; Knowledge; Lead; Learning; Link; Maintenance; Malignant Neoplasms; Measures; Medical; Methods; Mitotic; Mitotic Chromosome; Modeling; Molecular; Names; Normal Cell; Nucleotides; Operative Surgical Procedures; Patient-Focused Outcomes; Phase; Phenotype; Physical condensation; Population; Postdoctoral Fellow; Prognosis; Progress Reports; Proteins; Public Speaking; RNA; Regulator Genes; Research; Role; Route; Sampling; Single Nucleotide Polymorphism; Testing; The Cancer Genome Atlas; Tissues; Training; Transcript; Translating; Untranslated RNA; Work; articular cartilage; autosome; cancer cell; cancer genome; cancer risk; cancer type; chromosome conformation capture; chromosome missegregation; clinically significant; genome wide association study; genome-wide; insight; interest; lymphoblastoid cell line; member; novel diagnostics; novel therapeutic intervention; novel therapeutics; pre-doctoral; progenitor; programs; risk variant; skill acquisition; stem cells; targeted cancer therapy; therapy development; tool; tumor; tumor progression; virtual

Project Summary/Abstract: Genome instability is the most significant feature associated with poor prognosis in many cancers. But despite being a near-universal characteristic of human cancer, our knowledge of how genome instability initiates and contributes to tumor development is lacking. Because of its wide presence and close association with aggressive tumors, insight into the possible mechanisms and consequences of genome instability is crucial in the search for new and targeted cancer therapies and diagnostics. Here a new model is proposed, backed by significant preliminary findings, for the maintenance of genomic stability by cis-acting long non-coding RNA (lncRNA) elements that regulate multiple aspects of large-scale chromosome function. The main hypothesis of this project is that the recently discovered, cis-acting ASAR lncRNAs (ASynchronously Replicating Autosomal RNA), are expressed by normal cells on all autosomes to regulate fundamental chromosome behavior such as DNA replication timing, monoallelic gene expression, 3- dimensional chromosome localization, and mitotic chromosome condensation, but are frequently disrupted in cancer leading to genomic instability. Expression of the first two members of the ASAR family (ASAR6, ASAR15) is required for stability on chromosome 6 and 15 respectively, and disruption of either lncRNA leads to aberrant chromosomes through increased stalling of replication forks and mis-segregation of chromosomes. The long-term objective of this research is to identify all ASARs on human autosomes, validate their functional role in genome stability, and use ASARs as a tool to understand and ultimately identify and treat cancers with genomic instability. In Aim 1 a genome wide search for expression of putative ASARs will be performed utilizing a single-cell derived, haplotype-resolved human primary cell model system, followed by assessment of the functional qualities of potential ASARS with nucleotide sequencing assays that measure DNA replication timing, allele specific RNA expression, and 3D chromosome localization. To probe the potential effects of ASARs on human health, a search for significant disruption of ASARs in a dataset of ~10,000 human tumor samples will be performed. The research will be conducted as part of a comprehensive training plan involving advanced skill development in bioinformatics and biostatistics, professional development such as public speaking and networking, and will take place within an extensive intellectual community composed of cancer biologists at the Knight Cancer Institute, molecular and medical geneticists, and computational biologists at OHSU. The post-doctoral research direction will translate the knowledge of chromosome biology and skillsets in genomics developed during the pre-doctoral period to study the mechanisms of action of non protein-coding germline risk loci in human cancer. The successful results of the proposed research will reveal basic functions of chromosomes and provide new insight towards understanding genomic instability, a common abnormality in cancer.

项目概要/摘要：基因组不稳定性是与预后不良相关的最显著特征 在许多癌症中。但是，尽管这是人类癌症的一个几乎普遍的特征， 缺乏基因组不稳定性启动和促进肿瘤发展。由于其广泛的存在和 与侵袭性肿瘤密切相关，深入了解基因组的可能机制和后果 不稳定性在寻找新的和有针对性的癌症治疗和诊断中至关重要。 在这里，提出了一个新的模型，由重要的初步研究结果支持，用于维持基因组 顺式作用长链非编码RNA（lncRNA）元件调节大规模多个方面的稳定性 染色体功能该项目的主要假设是，最近发现的顺式作用ASAR lncRNA（A同步复制常染色体RNA）由正常细胞在所有常染色体上表达， 调节基本的染色体行为，如DNA复制时间，单等位基因表达，3- 三维染色体定位，有丝分裂染色体凝聚，但经常中断， 导致基因组不稳定的癌症。ASAR家族的前两个成员（ASAR 6， ASAR 15）分别是6号和15号染色体上的稳定性所必需的，并且 通过增加复制叉的停滞和染色体的错误分离而导致异常染色体。 本研究的长期目标是鉴定人类常染色体上的所有ASAR，验证其功能， 在基因组稳定性中的作用，并使用ASAR作为工具来了解并最终识别和治疗癌症。 基因组不稳定性在目标1中，将进行全基因组搜索以寻找推定的ASAR的表达 利用单细胞衍生的、单倍型分辨的人原代细胞模型系统，随后评估 利用核苷酸测序分析来测量DNA复制的潜在ASAR的功能质量 定时、等位基因特异性RNA表达和3D染色体定位。为了探测 ASAR对人类健康的影响，在约10，000例人类肿瘤的数据集中寻找ASAR的显著破坏 样品将进行。 这项研究将作为涉及高级技能开发的综合培训计划的一部分进行 在生物信息学和生物统计学，专业发展，如公开演讲和网络，并将 发生在一个广泛的知识界组成的癌症生物学家在骑士癌症 研究所，分子和医学遗传学家，和计算生物学家在OHSU。博士后研究 方向将翻译染色体生物学的知识和技能，在基因组学开发期间， 博士前阶段研究人类非蛋白编码生殖系风险基因座的作用机制 癌这项研究的成功结果将揭示染色体的基本功能， 为理解基因组不稳定性提供了新的见解，基因组不稳定性是癌症中的一种常见异常。