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Investigation of transcription factor binding sequences and target genes using protein binding microarrays.

机译：使用蛋白质结合微阵列研究转录因子结合序列和靶基因。

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摘要

This dissertation describes the investigation of binding rules and DNA binding sequences for several transcription factors (TFs). We develop Protein Binding Microarrays (PBMs) to study the interactions between TFs and DNA in vitro and we use a support vector machine (SVM) algorithm to capture these interactions in silico. We then apply this methodology to study the binding of TFs to promoters and repetitive sequences in a genomewide fashion.In Chapter 2, we thoroughly investigate HNF4alpha/DNA binding interactions using PBMs. We investigate binding specificities for various isoforms and species of HNF4alpha. We then use PBMs to rank &sim 4,000 HNF4alpha binding sequences in order of binding affinity. Using this training set we identify/predict novel HNF4alpha binding sequences and rules, and from these rules we generate a model for HNF4alpha binding. We then use this large dataset, in combination with ChIP-on-chip and RNAi followed by an expression profiling to identify hundreds of novel HNF4alpha direct target genes.In Chapter 3, we identify HNF4alpha association with Alu repeats, a novel finding. We investigate HNF4alpha binding to Alu sequences in in vitro and in vivo in the promoters of HNF4alpha-regulated genes, and thus reveal a novel association between HNF4alpha and Alu repeats.Finally in Chapter 4, we leverage the PBM technology to investigate the binding properties of transcription factors COUP-TF2 and TCF-1. We identify many sequences that bind both HNF4alpha and TCF-1 and those bind both HNF4alpha and COUP-TF2. This finding suggests competition between these TFs on the promoters of their target genes. Additionally, we investigate the effect of coregulator PGCalpha and the effect of the endogenous ligand, linoleic acid,on HNF4alpha DNA binding.This study significantly advances our knowledge of binding sequences, binding motifs, target genes, and transcriptional regulation for several transcription factors, HNF4alpha, COUP-TF2 and TCF-1. It also sheds light on evolution of HNF4alpha binding sequences through Alu repetitive elements. Finally, it provides a powerful framework for the comprehensive investigation of transcriptional regulation in mammalian systems for other transcription factors.
机译：本文介绍了几种转录因子（TFs）的结合规则和DNA结合序列的研究。我们开发蛋白质结合微阵列（PBM），以研究TF与DNA的体外相互作用，并使用支持向量机（SVM）算法在计算机中捕获这些相互作用。然后，我们将这种方法应用于研究全基因组中TF与启动子和重复序列的结合。在第二章中，我们使用PBM彻底研究了HNF4alpha / DNA结合相互作用。我们调查了各种同工型和HNF4alpha物种的结合特异性。然后，我们使用PBM按结合亲和力的顺序对4,000个HNF4alpha结合序列进行排名。使用此训练集，我们可以识别/预测新颖的HNF4alpha结合序列和规则，并根据这些规则生成HNF4alpha结合模型。然后，我们将这个大型数据集与芯片上芯片和RNAi结合使用，然后进行表达谱分析，以鉴定数百种新颖的HNF4alpha直接靶基因。在第3章中，我们鉴定了HNF4alpha与Alu重复序列的关联，这是一个新颖的发现。我们在HNF4alpha调控基因的启动子中研究了HNF4alpha在体外和体内与Alu序列的结合，从而揭示了HNF4alpha与Alu重复序列之间的新型关联。最后在第四章中，我们利用PBM技术研究了HNF4alpha与Alu重复序列的结合特性。转录因子COUP-TF2和TCF-1。我们确定了许多序列，既可以结合HNF4alpha和TCF-1，又可以结合HNF4alpha和COUP-TF2。这一发现表明这些TF在其靶基因的启动子之间的竞争。此外，我们研究了促成调节剂PGCalpha和内源性配体亚油酸对HNF4alpha DNA结合的影响。这项研究显着提高了我们对几种转录因子HNF4alpha的结合序列，结合基序，靶基因和转录调控的认识。 ，COUP-TF2和TCF-1。它还通过Alu重复元件阐明了HNF4alpha结合序列的进化。最后，它为全面研究哺乳动物系统中其他转录因子的转录调控提供了强大的框架。

著录项

  • 作者

    Bolotin, Eugene Leonidovich.;

  • 作者单位

    University of California, Riverside.;

  • 授予单位 University of California, Riverside.;
  • 学科 Biology Molecular.Biology Cell.Biology Bioinformatics.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 191 p.
  • 总页数 191
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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