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（申请人提供）：雄激素受体（AR）是一种配体依赖性转录因子，在前列腺癌的发生和进展中起关键作用，是治疗靶点。令人惊讶的是，很少有人知道AR结合，AR协作转录因子，以及人类基因组中AR靶基因的调控。该提案的总体目标是从全基因组角度研究雄激素依赖性（AD）和非依赖性（Al）前列腺癌细胞中AR及其协作转录因子对蛋白质编码基因和一类非编码基因（microRNA [miRNA]）的组合转录调控。为了解决这些问题，我们将使用染色质免疫沉淀（ChIP）结合人类全基因组询问平铺微阵列（ChIP芯片），研究在体内结合的转录因子和它们的调节功能，在AD和Al前列腺癌。我们的具体目标是：（1）确定AD和Al前列腺癌细胞中是否存在不同的AR结合、AR协作转录因子配偶体和AR靶基因。AR ChIP芯片测定将在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和实验验证。(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。将进行协同转录因子ChIP芯片，并将其与AR ChIP芯片和基因表达谱相关联，以鉴定AD和Al前列腺癌细胞中AR靶基因的组合转录调控代码。(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）ChIP芯片将在AD和Al前列腺癌细胞中进行。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前列腺癌细胞中差异转录因子调节的miRNA表达。总之，这些研究将增加我们对AD和Al前列腺癌中AR及其协作转录因子在全基因组水平上对靶编码和非编码基因的差异转录调控的基本理解，这将导致识别用于AD和Al前列腺癌治疗干预的新分子靶点。