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: 10553609
• 负责人: Ram Shankar Mani
• 金额: $ 38.46万
• 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/10553609
• 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; Epithelium; Event; Future; Gene Family; Gene Fusion; Gene Rearrangement; Genes; Genetic Transcription; Genome; Genomic Segment; Genomic approach; Genomics; 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; Oxidative Stress Induction; 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 Induction; 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; 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疾病的早期驱动事件 癌（PCa）。这些重排通常涉及雄激素调节的转录活性基因的融合。 基因与ETS基因（ERG、ETV 1、ETV 4和ETV 5）的融合，导致融合基因过表达。最 在>50%的PCa中观察到的普遍的ETS基因重排涉及雄激素的融合， 受体（AR）靶基因TMPRSS 2与ERG原癌基因，导致TMPRSS 2- ERG基因融合。定义与复发性基因组疾病形成相关的机制 重排将有助于我们对PCa病因的理解，并将影响PCa的几个方面。 临床疾病管理，包括预防、早期诊断和治疗目标。整体 该提案的目标是应用创新的基因组学方法来确定复发性基因组疾病的起源。 PCa中的重排。根据我们的工作和新兴的科学文献，我们假设 雄激素信号相关的3D基因组组织和转录调控有助于 基因组中的拓扑压力酶DNA拓扑异构酶II β（TOP 2B）解决拓扑压力 通过形成瞬时DNA双链断裂（DSB）。我们认为，氧化应激损害了 TOP 2B的功能，导致形成持久的DNA DSB。基因组中DNA DSB的聚集 增加了它们的错误修复和形成复发性基因组重排的可能性。在特定 目的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。我们将 利用这一知识来确定生殖系PCa易感风险SNP的机制， 体细胞结构变异改变了3D基因组结构以驱动PCa中的转录失调。在 具体目标2，我们将映射与拓扑压力相关的基因组区域，通过应用我们的新 确定TOP 2B占用率的战略。我们还将测试氧化应激和TDP 2的作用，TDP 2是一种5-prime 酪氨酰-DNA磷酸二酯酶在TOP 2B介导的DNA断裂形成中的作用。此外，我们将测试 假设TOP 2B介导的DNA DSB是非随机的，并且发生在不同的基因组区域， 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与前列腺上皮分化状态之间的关系。 以及TMPRSS 2-ERG基因融合体的形成。我们预计，成功实现这些目标将 增强我们对PCa中复发性基因组重排起源的理解。我们相信我们的 PCa模型的发现将对许多其他类型的癌症产生广泛的影响。重要的是这些 这些研究将作为未来旨在预防和治疗PCa的临床试验的理论基础。