Computer-assisted identification of cell cycle-related genes: new targets for E2F transcription factors

发起人 E2F型 转录因子 生物 染色质免疫沉淀 基因 计算生物学 Cis监管模块 细胞周期 基因调控网络 遗传学 响应元素 抄写(语言学) 基因表达调控 基因表达 细胞生物学 语言学 哲学
作者
Alexander Kel,Olga Kel‐Margoulis,Peggy J. Farnham,Stephanie M. Bartley,Edgar Wingender,Michael Q. Zhang
出处
期刊:Journal of Molecular Biology [Elsevier BV]
卷期号:309 (1): 99-120 被引量:173
标识
DOI:10.1006/jmbi.2001.4650
摘要

The processes that take place during development and differentiation are directed through coordinated regulation of expression of a large number of genes. One such gene regulatory network provides cell cycle control in eukaryotic organisms. In this work, we have studied the structural features of the 5′ regulatory regions of cell cycle-related genes. We developed a new method for identifying composite substructures (modules) in regulatory regions of genes consisting of a binding site for a key transcription factor and additional contextual motifs: potential targets for other transcription factors that may synergistically regulate gene transcription. Applying this method to cell cycle-related promoters, we created a program for context-specific identification of binding sites for transcription factors of the E2F family which are key regulators of the cell cycle. We found that E2F composite modules are found at a high frequency and in close proximity to the start of transcription in cell cycle-related promoters in comparison with other promoters. Using this information, we then searched for E2F sites in genomic sequences with the goal of identifying new genes which play important roles in controlling cell proliferation, differentiation and apoptosis. Using a chromatin immunoprecipitation assay, we then experimentally verified the binding of E2F in vivo to the promoters predicted by the computer-assisted methods. Our identification of new E2F target genes provides new insight into gene regulatory networks and provides a framework for continued analysis of the role of contextual promoter features in transcriptional regulation. The tools described are available at http://compel.bionet.nsc.ru/FunSite/SiteScan.html.
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