3D genome architecture and the origins of recurrent genomic rearrangements in prostate cancer

3D 基因组结构和前列腺癌中反复基因组重排的起源

• 批准号: 10328936
• 负责人: Ram Shankar Mani
• 金额: $ 39.24万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328936
• 关键词: 3-Dimensional; Androgen Receptor; Androgens; Architecture; Award; Basal Cell; Basic Science; Benign; Bromodomain; Cancer Etiology; Cells; Chromatin; Chromatin Interaction Analysis by Paired-End Tag Sequencing; Clinical; Clinical Data; Clinical Trials; DNA; DNA Double Strand Break; DNA Polymerase II; DNA Repair; DNA Sequence Rearrangement; Data; Data Set; Development; Disease Management; ERG gene; ETV1 gene; ETV4 gene; Early Diagnosis; Elements; Enzymes; Epithelial; Event; Future; Gene Family; Gene Fusion; Gene Rearrangement; Genes; Genetic Transcription; Genome; Genomic Segment; Genomic approach; Genomics; Germ Lines; Goals; Human; Impairment; In Vitro; Inflammation; Ionizing radiation; Journals; Knowledge; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; Methodology; Methods; Modeling; Outcome; Oxidative Stress; Paper; Pathway interactions; Population; Prevention; Process; Prostate; Prostate Cancer therapy; Proteins; Proto-Oncogenes; Publications; Publishing; RNA; Radical Prostatectomy; Reactive Oxygen Species; Recurrence; Regulation; Reporting; Research Personnel; Risk; Role; Science; Signal Transduction; Site; Source; Specimen; Stress; TMPRSS2 gene; Techniques; Testing; Therapeutic; Topoisomerase II; Transcriptional Regulation; Transplantation; Variant; Work; cancer genome; cancer type; causal variant; cell type; fusion gene; genome-wide; in vivo; innovation; insight; novel; overexpression; prostate cancer model; repaired; therapeutic target; transcription factor; tyrosyl-DNA phosphodiesterase

Genomic rearrangements involving the ETS transcription factor family genes are early driver events in prostate cancer (PCa). These rearrangements typically involve the fusion of androgen-regulated transcriptionally active genes with the ETS genes (ERG, ETV1, ETV4 and ETV5), resulting in fusion gene over-expression. The most prevalent ETS gene rearrangement, which is observed in >50% of PCa, involves the fusion of the androgen receptor (AR) target gene, TMPRSS2, with the ERG proto-oncogene, resulting in the formation of TMPRSS2- ERG gene fusion. Defining the mechanisms associated with the formation of recurrent genomic rearrangements will contribute towards our understanding of PCa etiology and will impact several aspects of clinical disease management ranging from prevention, early diagnosis and therapeutic targeting. The overall goal of this proposal is to apply innovative genomics approaches to define the origins of recurrent genomic rearrangements in PCa. On the basis of our work and the emerging body of scientific literature, we hypothesize that androgen signaling associated 3D genome organization and transcriptional regulation contribute towards topological stress in the genome. The enzyme DNA topoisomerase II beta (TOP2B) resolves topological stress by the formation of transient DNA double strand breaks (DSBs). We suggest that oxidative stress impairs the function of TOP2B, resulting in the formation of persistent DNA DSBs. Clustering of DNA DSBs in the genome increases the likelihood of their mis-repair and the formation of recurrent genomic rearrangements. In Specific Aim 1, we will define the AR-induced, transcription-associated chromatin interactions in PCa models. We will leverage this knowledge to pinpoint the mechanisms by which germ-line PCa predisposing risk SNPs and somatic structural variations alter the 3D genome architecture to drive transcriptional dysregulation in PCa. In Specific Aim 2, we will map the genomic regions associated with topological stress by applying our new strategy to identify TOP2B occupancy. We will also test the role of oxidative stress and TDP2, a 5-prime tyrosyl-DNA phosphodiesterase in the formation of TOP2B mediated DNA breaks. Furthermore, we will test the hypothesis that TOP2B mediated DNA DSBs are non-random and occur at distinct genomic regions in the various cell types of the prostate—dictated in part by transcription-associated 3D genome architecture. Therefore, in Specific Aim 3, we will unravel the relationship between prostate epithelial differentiation status and the formation of TMPRSS2-ERG gene fusions. We anticipate that successful completion of these aims will enhance our understanding of the origins of recurrent genomic rearrangements in PCa. We believe that our discoveries in PCa models will have broad implications for many other types of cancers. Importantly, these studies will serve as the rationale for future clinical trials aimed towards the prevention and treatment of PCa.

涉及 ETS 转录因子家族基因的基因组重排是前列腺的早期驱动事件 这些重排通常涉及雄激素调节的转录活性的融合。 基因与 ETS 基因（ERG、ETV1、ETV4 和 ETV5），导致融合基因过度表达。 在 >50% 的 PCa 中观察到普遍的 ETS 基因重排，涉及雄激素的融合 受体（AR）靶基因TMPRSS2与ERG原癌基因结合，导致TMPRSS2-的形成 ERG基因融合的定义与复发基因组形成相关的机制。 重新排列将有助于我们对 PCa 病因学的理解，并将影响以下几个方面： 临床疾病管理包括预防、早期诊断和治疗目标。 该提案的目标是应用创新的基因组学方法来定义循环基因组学的起源 基于我们的工作和新兴的科学文献，我们勇敢地进行了 PCa 的重新排列。 雄激素信号传导相关的 3D 基因组组织和转录调控有助于 DNA 拓扑异构酶 II beta (TOP2B) 可以解决基因组中的拓扑应力。 我们认为氧化应激会损害DNA双链断裂（DSB）。 TOP2B 的功能，导致基因组中持久 DNA DSB 的形成。 增加了它们错误修复和反复基因组重排形成的可能性。 目标 1，我们将在 PCa 模型中定义 AR 诱导的、转录相关的染色质相互作用。 利用这些知识来查明种系 PCa 诱发风险 SNP 和 体细胞结构变异改变了 3D 基因组结构，导致 PCa 中的转录失调。 具体目标 2，我们将通过应用我们的新方法绘制与拓扑应力相关的基因组区域图 我们还将测试氧化应激和 TDP2（5 素数）的作用。 酪氨酰-DNA 磷酸二酯酶在 TOP2B 介导的 DNA 断裂形成中的作用此外，我们将测试 假设 TOP2B 介导的 DNA DSB 是非随机的，并且发生在不同基因组区域 前列腺的各种细胞类型——部分由转录相关的 3D 基因组结构决定。 因此，在具体目标3中，我们将阐明前列腺上皮分化状态之间的关系 我们预计这些目标将成功完成。 增强我们对 PCa 中反复基因组重排起源的理解。 PCa 模型的发现将对许多其他类型的癌症产生广泛的影响。 研究将为未来旨在预防和治疗 PCa 的临床试验提供依据。