Impact of Coding Variation on Transcription Factor - DNA Recognition

摘要 序列特异性转录因子(TF)与其识别位点的结合是一种 基因调控的第一步。DNA结合的深入表征 转录因子的特异性对于理解转录调控是如何进行的至关重要 指定的。过去十年开发的用于TF的高度并行分析的技术 DNA结合特性已被用来研究转铁蛋白的DNA结合特性 来自各种TFDNA结合域(DBD)结构类(例如，同源域) 和物种。然而，尽管产生了这些大型数据集，但详细的 对于大多数转铁蛋白来说，对转铁蛋白-DNA结合特异性决定因素的了解仍然缺乏。 疾病突变和自然发生的编码变异，特别是那些 在DBD中，具有改变Tf DNA结合活性的潜力。然而，还有 对转铁蛋白-DNA结合活性的决定因素了解不足 准确预测这种编码突变对DNA结合活性的影响。这 是一个重要的问题，因为破坏转铁蛋白DNA的突变或编码变异 结合活性有可能扰乱1,000个基因的调节 人类基因组。 这个项目的目标是研究新的DNA结合活性决定因素 人类转录因子的主要结构类别，以确定异二聚体蛋白如何配对 可能调节Tf编码变体对DNA结合活性的影响，并 确定破坏固有Tf-DNA的编码变异的程度 识别改变了转铁蛋白的基因组靶向和基因调控。我们期待着我们的结果 数据集将揭示TF-DNA结合特异性的决定因素，确定 突变破坏DNA结合的特异性或亲和力，影响未来对 外显子组和全基因组序列数据，并开辟了新的研究领域 转录因子编码变异对转录基因调控和人类影响的研究 表型。

ABSTRACT Binding by sequence-specific transcription factors (TFs) to their recognition sites is a primary step in gene regulation. In-depth characterization of the DNA binding specificities of TFs is essential for understanding how transcriptional regulation is specified. Technologies developed in the past decade for highly parallel analysis of TF DNA binding specificities have been used to survey the DNA binding specificities of TFs from a variety of TF DNA binding domain (DBD) structural classes (e.g., homeodomains) and species. Nevertheless, despite the generation of these large datasets, a detailed understanding of TF-DNA binding specificity determinants is still lacking for most TFs. Disease mutations and naturally occurring coding variation in TFs, especially those within DBDs, have the potential to alter TF DNA binding activity. However, there is insufficient understanding of the determinants of TF-DNA binding activity to allow for accurate prediction of the effects of such coding mutations on DNA binding activity. This is an important problem, since mutations or coding variation that damage TF DNA binding activity have the potential to disrupt the regulation of 1,000s of genes in the human genome. The goals of this project are to investigate novel DNA binding activity determinants for major structural classes of human TFs, to determine how heterodimeric protein partners might modulate the effects of TF coding variants on DNA binding activity, and to determine the extent to which coding variation that damages intrinsic TF-DNA recognition alters TF genomic targeting and gene regulation. We anticipate our results and datasets will reveal determinants of TF-DNA binding specificity, identify what mutations damage DNA binding specificity or affinity, inform future interpretations of exome and whole-genome sequence data, and open new areas of investigation into studies of how TF coding variation impacts transcriptional gene regulation and human phenotypes.