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

涉及ETS转录因子家族基因的基因组重排是前列腺癌的早期驱动事件 癌症(PCA)。这些重排通常涉及雄激素调节的转录活性的融合 与ETS基因(ERG、ETV1、ETV4和ETV5)结合，导致融合基因过度表达。最多的 常见的ETS基因重排，在50%的前列腺癌中观察到，涉及雄激素的融合 受体(AR)靶基因TMPRSS2与ERG原癌基因，导致TMPRSS2- ERG基因融合。确定与循环基因组形成相关的机制 重新安排将有助于我们对PCA病因的理解，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。整体而言 这项提议的目标是应用创新的基因组学方法来确定重复性基因组的起源 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 基因组中的拓扑应力。DNA拓扑异构酶IIβ(TOP2B)分解拓扑应力 通过形成瞬时DNA双链断裂(DSB)。我们认为，氧化应激损害了 TOP2B的功能，导致持续DNA双链断裂的形成。基因组中DNA双链断裂的聚集性 增加了它们错误修复和形成经常性基因组重排的可能性。具体而言 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。我们会 利用这一知识来确定胚系PCA易感风险SNPs和 体细胞结构变异改变3D基因组结构以驱动PCA中的转录失调。在……里面 具体目标2，我们将通过应用我们的新技术绘制与拓扑应力相关的基因组区域 确定TOP2B占有率的策略。我们还将测试氧化应激和TDP2的作用，TDP2是一种5- 酪氨酰DNA磷酸二酯酶在TOP2B介导的DNA断裂中的形成。此外，我们还将测试 假设TOP2B介导的DNADSB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，在特定的目标3中，我们将揭开前列腺上皮分化状态之间的关系 TMPRSS2-ERG基因融合的形成。我们预计，这些目标的成功实现将 增强我们对前列腺癌反复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前列腺癌的临床试验的基础。

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.