Genome-Wide Analysis of Transcription Factor Function in Prostate Cancer

前列腺癌转录因子功能的全基因组分析

基本信息

批准号：
7314999
负责人：
Qianben Wang
金额：
$ 9万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-22 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7314999
关键词：
Address Algorithms Androgen Receptor Androgens Binding Binding Sites Bioinformatics Biological Assay Cancer Cell Growth Chromosomes Chromosomes, Human, Pair 21 Clinical Data Code Computer Simulation DNA DNA Polymerase II Data Analyses Elements Feasibility Studies GATA2 transcription factor Gene Expression Gene Targeting Genes Genome Goals Growth Human Human Genome LNCaP Lead Ligands Malignant neoplasm of prostate Maps Molecular Profiling Molecular Target Nucleic Acid Regulatory Sequences Oligonucleotide Microarrays PC3 cell line Phase Play Recruitment Activity Regulation Research Research Personnel Role Sampling Therapeutic Intervention Transcription Coactivator Transcriptional Regulation Validation cancer cell chromatin immunoprecipitation clinically relevant combinatorial experimental analysis genome-wide analysis improved in vivo novel programs promoter receptor binding therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): The androgen receptor (AR), a ligand-dependent transcription factor, plays a key role in the onset and progression of prostate cancer and is a therapeutic target. Surprisingly little is known of AR binding, AR collaborating transcription factors, and regulation of AR target genes in the human genome. The overall goal of this proposal is to improve our understanding of the combinatorial transcriptional regulation of target genes by AR, its collaborating transcription factors and its coactivators from a genome-wide view in androgen-dependent (AD) and -independent (Al) prostate cancer cells. To address these issures, we will use chromatin immunoprecipitation (ChIP) combined with human whole genome interrogating tiling microarrays (ChlP-on-chip) to study in vivo binding of transcription factors and their regulatory function in AD and Al prostate cancer. Our specific aims are to: (1) Determine whether distinct AR binding, AR collaborating transcription factor partners and AR target genes exist in AD and Al prostate cancer cells. AR ChlP-on-chip assays will be performed in AD and Al prostate cancer cells. AR binding, its collaborating transcription factors and AR target genes will be predicted by bioinformatics algorithms and experimentally validated. (2) Determine how AR and its collaborating transcription factors combinatorially regulate AR target genes in AD and Al prostate cancer cells. Collaborating transcription factor ChlP-on-chip will be performed and correlated with AR ChlP-on-chip and gene expression profiles to identify combinatorial transcriptional regulatory codes and mechanisms for AR target genes in AD and Al prostate cancer cells. The combinatorial regulation results from prostate cancer cell lines will be correlated with mircroarray data from clinical samples to verify clinical relevance. (3) Determine how coactivators play coregulatory roles in selected novel AR target genes identified from aim 1 and aim 2. The physical interactions among coactivators, AR and collaborating factors will be studied. The functional roles of coactivators in AR and collaborating factors binding, target gene expression and prostate cancer cell growth and survival will be determined. These studies will define the mechanisms underlying the differential transcriptional regulation of target genes by AR, collaborating transcription factors and coactivators in AD and Al prostate cancer and will lead to the identification of new molecular targets for therapeutic intervention.

描述（由申请人提供）：雄激素受体（AR）是配体依赖性转录因子，在前列腺癌的发作和进展中起关键作用，并且是治疗靶标。令人惊讶的是，对AR结合，AR协作转录因子以及人类基因组中AR靶基因的调节知之甚少。该提案的总体目标是通过AR，其协作转录因子及其共激活因子从雄激素依赖性（AD）（AD）和 - 独立的（AL）前列腺癌细胞中从基因组全基因组观察中提高对靶基因组合基因组合调节的理解。为了解决这些ISS，我们将使用染色质免疫沉淀（CHIP）结合人类的整个基因组询问瓷砖微阵列（CHLP-on-Chip）来研究转录因子的体内结合及其在AD和Al Prostate癌中的调节功能。我们的具体目的是：（1）确定AD和AL前列腺癌细胞中是否存在不同的AR结合，AR协作转录因子伙伴和AR靶基因。 AR CHLP片分析将在AD和AL前列腺癌细胞中进行。 AR结合，其协作转录因子和AR靶基因将通过生物信息学算法预测，并通过实验验证。（2）确定AR及其协作转录因子如何组合调节AD和Al前列腺癌细胞中的AR靶基因。将执行合作转录因子CHLP-n-CHIP与AR CHLP-on-ChIP和基因表达曲线相关联，以鉴定AD和Al Prostate癌细胞中AR靶基因的组合转录调节代码和机制。前列腺癌细胞系的组合调节结果将与临床样品中的miRCROARRAY数据相关，以验证临床相关性。（3）确定共激活因子如何在AIM 1和AIM 2中鉴定出的选定的新型AR靶基因中扮演核类角色。将研究共激活因子，AR和协作因素之间的物理相互作用。共激活因子在AR和协作因子结合，靶基因表达和前列腺癌细胞生长和存活中的功能作用。这些研究将定义AR，AD和AL前列腺癌中的转录因子和共激活因子对靶基因差异转录调控的基础机制，并将导致鉴定用于治疗干预的新分子靶标。