Impact of Coding Variation on Transcription Factor - DNA Recognition

编码变异对转录因子 - DNA 识别的影响

基本信息

批准号：
9923713
负责人：
MARTHA L BULYK
金额：
$ 79.06万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923713
关键词：
Affinity Alleles Area Benign Binding Binding Sites Biochemical Biological Assay Cells ChIP-seq Code Collaborations Computer Analysis Consult Consultations DNA DNA Binding DNA Binding Domain DNA Damage DNA Sequence Data Data Set Disease Exhibits Fibrinogen Future Gene Expression Regulation Generations Genes Genetic Transcription Genetic Variation Genome Genomics Genotype Goals Human Human Genome In Vitro Individual Intrinsic factor Investigation Letters Mutation Phenotype Positioning Attribute Proteins Regulation Regulator Genes Series Site Specific qualifier value Specificity Structure Surveys Technology Transcription Factor 3 Transcriptional Regulation Translating Variant Work cell type cofactor exome experimental study genome sequencing homeodomain in vitro activity in vivo large datasets novel precise genome editing scale up tool transcription factor transcriptome sequencing whole genome

项目摘要

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.

抽象的通过序列特异性转录因子（TFS）与其识别位点结合是一个基因调控的主要步骤。 DNA结合的深入表征 TF的特异性对于理解转录调节的特殊性至关重要指定的。在过去十年中开发的技术用于高度平行TF DNA结合特异性已用于调查TFS的DNA结合特异性来自各种TF DNA结合结构域（DBD）结构类别（例如，同源域）和物种。但是，尽管产生了这些大数据集，但详细对于大多数TF，仍然缺乏对TF-DNA结合特异性决定因素的理解。疾病突变和TF中的自然编码变化，尤其是那些在DBD中，有可能改变TF DNA结合活性。但是，有对TF-DNA结合活性的决定因素不足以允许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，因为突变或编码变化会损害TF DNA 结合活性有可能破坏对1000种基因的调节人基因组。该项目的目标是研究新颖的DNA结合活性决定因素人类TF的主要结构类别，以确定异二聚体蛋白伴侣如何可能会调节TF编码变体对DNA结合活性的影响，并确定损害固有TF-DNA的编码变化的程度识别会改变TF基因组靶向和基因调节。我们预计我们的结果数据集将揭示TF-DNA结合特异性的决定因素，确定什么突变损害DNA结合特异性或亲和力，为将来的解释提供信息外显子和全基因组序列数据，并开放新的调查领域关于TF编码变化如何影响转录基因调控和人类的研究表型。