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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：
10368951
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 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10368951
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 Series Site Specific qualifier value Specificity Surveys Technology Transcription Factor 3 Transcriptional Regulation Translating Variant Work cell type cofactor exome experimental study gene regulatory network 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.

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指定的.过去十年发展的TF高度并行分析技术 DNA结合特异性已被用于调查TF的DNA结合特异性从多种TF DNA结合结构域（DBD）结构类别（例如，同源结构域）和物种。然而，尽管产生了这些大型数据集，对于大多数TF，仍然缺乏对TF-DNA结合特异性决定簇的理解。疾病突变和TF中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。不过有对TF-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，因为突变或编码变异，结合活性有可能破坏1,000个基因的调控，人类基因组本项目的目标是研究新的DNA结合活性决定簇，主要结构类别的人TF，以确定如何异二聚体蛋白伴侣可能调节TF编码变体对DNA结合活性的影响，确定编码变异破坏内在TF-DNA的程度识别改变TF基因组靶向和基因调控。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，突变损害DNA结合特异性或亲和力，为未来的解释提供信息。外显子组和全基因组序列数据，并开辟了新的研究领域，研究TF编码变异如何影响转录基因调控和人类表型