Systems analysis of the prostate cancer epigenome

前列腺癌表观基因组的系统分析

• 批准号: 10043686
• 负责人: Zhong Chen
• 金额: $ 19.83万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-14 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10043686
• 关键词: ATAC-seq; Ablation; Algorithms; Androgen Antagonists; Androgen Receptor; Androgens; Area; Award; Binding; Binding Sites; Biological Assay; Cancer Patient; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Computer Models; Data; Data Set; Development; Enhancers; Environment; Epigenetic Process; Event; Funding; Genomics; Goals; Growth; Hormones; Laboratories; Learning; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular and Cellular Biology; Morbidity - disease rate; Nucleosomes; Patients; Pattern; Positioning Attribute; Prostate Cancer therapy; Proteomics; Research; Resistance; Resistance development; Role; Series; Specialist; System; Systems Analysis; Techniques; Therapeutic; Tissues; Transcriptional Regulation; Translations; Work; advanced prostate cancer; anticancer research; base; cancer cell; chromatin remodeling; design; epigenome; epigenome editing; epigenomics; experimental study; genetic regulatory protein; genome-wide; hormone therapy; innovation; member; novel; programs; prostate cancer cell; prostate cancer progression; receptor binding; targeted treatment; therapy resistant; tool; transcription factor; transcriptome sequencing

Project Summary/Abstract Although androgen ablation is initially effective for advanced prostate cancer treatment, resistance ultimately develops through various mechanisms, causing patient morbidity. Systems analysis of the prostate cancer epigenome is a genome-scale approach to understanding the under-studied epigenetic events that characterize prostate cancer progression to the resistant state. This proposed work is an integral part of the NCI-funded research program U54 CA217297, which focuses on studying epigenetic mechanisms exploited by hormone- resistant cancer cells to acquire growth and invasion advantages. Dr. Qianben Wang’s laboratory has recently performed an integrative analysis of strand specific paired-end ChIP-exo (ChIP-ePENS) and MNase-seq data and discovered an epigenetic mechanism by which genomic and transcriptional regulation are controlled by precise changes to nucleosome positioning within transcription factor (TF) binding sites. This represents the latest in a series of findings that have come out of the work of the research specialist, Dr. Zhong Chen, as the only key, senior member of the Wang laboratory. Dr. Chen facilitated this breakthrough by developing the ChIP- ePENS assay and working with colleagues to develop a new algorithm to perform integrative analysis of ChIP- ePENS and MNase-seq data. The intersection of these innovative techniques led to the identification of unique footprint boundary patterns (FBPs) of TF binding that determine how nucleosomes are positioned in and around androgen receptor (AR)-bound enhancers. Additional evidence that AR bound by anti-androgen activates enhancers with unique FBPs suggested that this epigenetic mechanism is hijacked by hormone-resistant cancer cells for AR redeployment under a therapeutic condition. The U54 project will determine the role of nucleosome repositioning as well as its regulatory proteins in supporting AR redeployment for hormone-resistant prostate cancer. Dr. Chen will be responsible for: (1) generating the high-throughput ChIP-ePENS, MNase-seq, ATAC- seq and RNA-seq datasets from prostate cancer cells and patient tissues; (2) analyzing sequencing data and participating in the development of computational models to assess nucleosome positioning and spacing; and (3) performing molecular and cellular biology experiments including developing novel CRISPR-dCas9-based editing tools to study nucleosome positioning and prostate cancer progression, and using proteomics to identify transcription factors and chromatin remodelers regulating nucleosome positioning. He will design and utilize a functional omics-oriented CRISPR/dCas9-based system for therapeutic prostate cancer epigenome editing, opening up new areas of research in the Wang lab while facilitating the translation of the U54 epigenetic discoveries into therapeutic tools and clinical benefits. The Research Specialist award would provide a stable and ideal research environment in which to pursue his goals in genomic and epigenomic cancer research and to open up a range of opportunities to develop targeted therapies for hormone-resistant cancers.

项目摘要/摘要 尽管雄激素消融最初对晚期前列腺癌治疗有效，但最终抗药性 通过各种机制的发展，导致患者发病率。前列腺癌的系统分析 表观基因组是一种理解表征不足的表观遗传事件的基因组规模方法 前列腺癌发展到抗性状态。这项拟议的工作是NCI资助的组成部分 研究计划U54 CA217297，该计划的重点是研究本人探索的表观遗传机制 抵抗癌细胞获得生长和侵袭的优势。 Qianben Wang博士最近有 对链特异性配对芯片-EXO（芯片epens）和MNase-seq数据进行了集成分析 并发现了一种表观遗传机制，通过该机制，基因组和转录调节受到控制 转录因子（TF）结合位点内的核体定位的精确变化。这代表 最新的一系列研究结果中，研究专家郑陈的工作是 唯一的关键，王实验室的高级成员。 Chen博士通过开发芯片来准备了这一突破 Epens分析并与同事合作开发一种新算法，以进行芯片的综合分析 Epens和Mnase-Seq数据。这些创新技术的交集导致了独特的识别 TF结合的足迹边界模式（FBP）决定了核小体的位置和周围的位置 雄激素受体（AR）结合增强子。抗雄激素约束的AR激活的其他证据 具有独特FBP的增强剂表明，这种表观遗传机制被抗激素癌劫持 在治疗条件下进行AR重新部署的细胞。 U54项目将确定核小体的作用 重新定位及其调节蛋白在支持抗马龙前列腺的AR重新部署方面 癌症。 Chen博士将负责：（1）产生高通量芯片芯片，MNase-Seq，ATAC- 来自前列腺癌细胞和患者组织的SEQ和RNA-SEQ数据集； （2）分析测序数据和 参与计算模型的开发以评估核病组的定位和间距；和 （3）进行分子和细胞生物学实验，包括开发基于新型的CRISPR-DCAS9 编辑研究核小体定位和前列腺癌进展的工具，并使用蛋白质组学识别 转录因子和染色质重塑器调节核病的定位。他将设计并利用 基于功能上的OMICS CRISPR/DCAS9用于治疗前列腺癌表观基因组编辑的系统， 在支持U54表观遗传学的翻译的同时，在王实验室中开放新的研究领域 发现治疗工具和临床益处。研究专家奖将提供一个稳定的 以及在基因组和表观基因组癌症研究中追求目标的理想研究环境以及 为开发耐药癌的有针对性疗法的机会开放。