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

• 批准号: 7886586
• 负责人: Qianben Wang
• 金额: $ 24.78万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-22 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886586
• 关键词: Address; Algorithms; Androgen Receptor; Androgens; Binding; Binding Sites; Bioinformatics; Biological Assay; Cell Proliferation; Chromosomes; Chromosomes, Human, Pair 21; Code; Computer Simulation; DNA Polymerase II; DNA Sequence; Data; Data Analyses; Elements; Feasibility Studies; Functional RNA; GATA2 transcription factor; Gene Expression; Gene Targeting; Genes; Genome; Goals; Growth; Human Genome; LNCaP; Lead; Ligands; Malignant neoplasm of prostate; Maps; Mentors; MicroRNAs; Molecular Profiling; Molecular Target; Nucleic Acid Regulatory Sequences; Oligonucleotide Microarrays; Phase; Play; Polymerase; Proteins; RNA Polymerase II; Recruitment Activity; Regulation; Research; Role; TMPRSS2 gene; Therapeutic Intervention; Transcriptional Regulation; Validation; cancer cell; chromatin immunoprecipitation; clinically relevant; combinatorial; gene discovery; genome wide association study; genome-wide; genome-wide analysis; improved; in vivo; novel; promoter; receptor binding; therapeutic target; transcription factor

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 investigate the combinatorial transcriptional regulation of protein-coding genes and a class of non-coding genes (microRNA [miRNA]) by AR and its collaborating transcription factors from a genome-wide view in androgen-dependent (AD) and -independent (Al) prostate cancer cells. To address these issues, 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 factors ChlP-on-chip will be performed and correlated with AR ChlP-on-chip and gene expression profiles to identify combinatorial transcriptional regulatory codes for AR target genes in AD and Al prostate cancer cells. (3) Determine whether AR and its collaborating transcription factors regulate miRNAs in AD versus Al prostate cancer cells. RNA polymerase II (pol II) ChlP-on-chip will be performed in AD and Al prostate cancer cells. Pol II binding will be correlated to AR and its collaborating transcription factors bindings and miRNA expression profiles to identify differential transcription factors-regulated miRNA expression in AD and Al prostate cancer cells. In summary, these studies will increase our fundamental understanding of differential transcriptional regulation of target coding and non-coding genes by AR and its collaborating transcription factors on a genome-wide level in AD and Al prostate cancer, which will lead to identification of new molecular targets for therapeutic intervention in AD and Al prostate cancer.

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。该提案的总体目的是通过AR研究蛋白质编码基因的组合转录调节和一类非编码基因（microRNA [miRNA]）及其从雄激素依赖性（AD）和 - 独立（AL）（Al）前列腺癌细胞中从基因组全基因组视图中的合作转录因子进行研究。为了解决这些问题，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。将进行合作转录因子CHLP-n-ChIP和与AR芯片和基因表达曲线相关联，以鉴定AD和AL前列腺癌细胞中AR靶基因的组合转录调节代码。 （3）确定AR及其协作转录因子是否调节AD与Al前列腺癌细胞中的miRNA。 RNA聚合酶II（POL II）将在AD和AL前列腺癌细胞中进行CHLP--CHIP。 Pol II结合将与AR及其协作转录因子结合和miRNA表达谱相关，以鉴定AD和AL前列腺癌细胞中受差异转录因子调节的miRNA表达。总而言之，这些研究将提高我们对AR及其在AD和AL前列腺癌中基因组范围内的合作转录因子对靶标编码和非编码基因的差异转录调控的基本理解，这将导致鉴定AD和AL PROSOSTATE癌症和AL PROSOSTATE癌症的新分子靶标。