Systems analysis of the prostate cancer epigenome

前列腺癌表观基因组的系统分析

• 批准号: 10238851
• 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/10238851
• 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 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; refractory cancer; 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.

项目概要/摘要 尽管雄激素消融最初对晚期前列腺癌治疗有效，但最终会产生耐药性 通过各种机制发展，导致前列腺癌患者发病。 表观基因组是一种基因组规模的方法，用于了解未充分研究的表观遗传事件，这些事件表征 这项提议的工作是 NCI 资助的一个组成部分。 研究计划 U54 CA217297，重点研究激素利用的表观遗传机制 王千本博士的实验室最近发现了抵抗癌细胞获得生长和侵袭优势的方法。 对链特异性配对末端 ChIP-exo (ChIP-ePENS) 和 MNase-seq 数据进行综合分析 并发现了基因组和转录调控的表观遗传机制 转录因子 (TF) 结合位点内核小体定位的精确变化。 研究专家陈忠博士的一系列研究成果中的最新成果 Wang 实验室唯一的关键高级成员 Chen 博士通过开发 ChIP- 促进了这一突破。 ePENS 测定并与同事合作开发一种新算法来执行 ChIP 的综合分析 ePENS 和 MNase-seq 数据的交叉导致了独特的识别。 TF 结合的足迹边界模式 (FBP)，决定核小体如何定位在其内部和周围 雄激素受体 (AR) 结合增强剂的更多证据表明 AR 与抗雄激素结合激活。 具有独特FBP的增强子表明这种表观遗传机制被激素抵抗性癌症劫持 U54项目将确定核小体的作用。 重新定位及其调节蛋白支持激素抵抗性前列腺的 AR 重新部署 陈博士将负责：(1) 生成高通量 ChIP-ePENS、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 参与开发评估核小体定位和间距的计算模型；以及 (3) 进行分子和细胞生物学实验，包括开发基于 CRISPR-dCas9 的新型 编辑工具来研究核小体定位和前列腺癌进展，并使用蛋白质组学来识别 他将设计和利用调节核小体定位的转录因子和染色质重塑因子。 基于功能组学的 CRISPR/dCas9 系统，用于治疗性前列腺癌表观基因组编辑， 为 Wang 实验室开辟新的研究领域，同时促进 U54 表观遗传学的转化 研究专家奖将提供稳定的治疗工具和临床益处的发现。 以及实现基因组和表观基因组癌症研究目标的理想研究环境 为开发激素抵抗性癌症的靶向疗法开辟一系列机会。