Computational Models for Mechanisms of Global Transcription Regulation

描述（由申请人提供）：来自Affymetrix， Agilent和Nimblgen的全基因组平片阵列允许生物学家进行无偏倚的染色质免疫沉淀，结合DNA微阵列分析（chlp芯片）来研究转录因子（tf）在体内结合的基因组水平。然而，平铺阵列上的chlp芯片也会产生大量的数据，这对分析算法的开发提出了挑战。我们建议开发有效的计算算法来分析基因组平铺阵列上的chlp芯片实验，并模拟全球转录调控机制，使生物学家能够利用chlp芯片来揭示哺乳动物基因组中的转录调控网络。

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.