Computational Models for Mechanisms of Global Transcription Regulation

全球转录调控机制的计算模型

• 批准号: 7923261
• 负责人: Xiaole Shirley Liu
• 金额: $ 39.61万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2011-09-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923261
• 关键词: Adopted; Algorithms; Behavior; Binding; Boxing; Breast Cancer Cell; Breast Carcinoma; Chromatin; Collaborations; Computational Biology; Computational algorithm; Computer Simulation; Computer software; Coupled; DNA Microarray Chip; Dana-Farber Cancer Institute; Data; Databases; Development; Estrogen Receptors; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Genome; Genomics; Goals; Human; Immunoprecipitation; Internet; Java; Laboratories; Linear Models; Maps; Masks; Methods; Microarray Analysis; Micrococcal Nuclease; Modeling; Molecular Conformation; Molecular Profiling; Nucleosomes; Nucleotides; Occupations; Performance; Polymerase; Procedures; Protocols documentation; Qualifying; RNA Polymerase II; Receptor Gene; Regulation; Research; Research Personnel; Scanning; Sequence Analysis; Techniques; Technology; Testing; Time; Tissue-Specific Gene Expression; Transcriptional Regulation; Validation; Western Blotting; Width; Work; acronyms; base; chromatin immunoprecipitation; combinatorial; design; genome-wide; improved; in vivo; mammalian genome; markov model; open source; programs; promoter; research study; statistics; tool; transcription factor; user-friendly

DESCRIPTION (provided by applicant): Whole genome tiled arrays from Affymetrix, Agilent, and Nimblgen allow biologists to conduct unbiased chromatin immunoprecipitation coupled with DNA microarray analysis (ChlP-chip) to study the genome level in vivo binding of transcription factors (TFs). However, ChlP-chip on tiled arrays also generates massive amount data and poses a challenge for analysis algorithm development. We propose to develop effective computational algorithms to analyze ChlP-chip experiments on genome tiled arrays and model global transcription regulation mechanisms, for the goal of allowing biologists to adopt ChlP-chip to unravel the transcription regulatory network in mammalian genomes. Our specific aims are as follows. (1) Develop an open-source model-based algorithm to identify genomic regions enriched by TF ChlP-chip on Affymetrix tiled arrays. The approach will work with single ChlP-chip replicate without using mismatch probes or control experiments. (2) Analyze performance variability introduced in ChlP-chip procedures, tiled array platforms, and analysis methods. (3) Implement a public web server with integrated tools for sequence analysis of the global ChlP-regions in mammalian genomes. (4) Identify TF's cooperative binding partners and regulated genes, and model its global mechanisms of transcription regulation. Through highly collaborative efforts between computational and experimental biologists, including ChlP-chip, gene expression profiling, nucleosome occupation, and motif analyses, we will study estrogen receptor regulation in breast cancer cells. The proposed project will significantly enhance our understanding of global transcription regulatory mechanisms in mammalian genomes. Aim 4 will help answer the question what genes in breast carcinoma are regulated by estrogen receptor and why.

描述（由申请人提供）：来自Affymetrix，Agilent和Nimblgen的整个基因组瓷砖阵列允许生物学家进行无偏的染色质免疫沉淀，并与DNA微阵列分析（CHLP-CHIP）结合，研究转录因子的体内基因组水平（TFS）。但是，瓷砖阵列上的CHLP芯片也会产生大量数据，并为分析算法开发带来挑战。我们建议开发有效的计算算法，以分析有关基因组瓷砖阵列的CHLP-CHIP实验，并模拟全局转录调控机制，目的是允许生物学家采用CHLP-CHIP来揭示哺乳动物基因组中的转录调节网络。 我们的具体目标如下。 （1）开发一种基于开源模型的算法，以识别Affymetrix瓷砖阵列中TF CHLP-CHIP富含的基因组区域。该方法将与单个CHLP-CHIP复制一起使用，而无需使用不匹配探针或对照实验。 （2）分析CHLP-CHIP程序，瓷砖阵列平台和分析方法中引入的性能变异性。 （3）实施一个公共Web服务器，该服务器具有集成工具，用于对哺乳动物基因组中全局CHLP区域进行序列分析。 （4）确定TF的合作结合伙伴和调节基因，并建模其全球转录调节机制。通过计算和实验生物学家之间的高度协作努力，包括CHLP芯片，基因表达分析，核小体占用和基序分析，我们将研究乳腺癌细胞中的雌激素受体调节。 拟议的项目将显着增强我们对哺乳动物基因组中全球转录调节机制的理解。 AIM 4将有助于回答以下问题，哪些乳腺癌中的基因受雌激素受体的调节以及原因。