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.

抽象的序列特异性转录因子 (TF) 与其识别位点的结合是基因调控的第一步。 DNA 结合的深入表征转录因子的特异性对于理解转录调控的机制至关重要指定的。过去十年开发的用于 TF 高度并行分析的技术 DNA 结合特异性已用于调查 TF 的 DNA 结合特异性来自各种 TF DNA 结合域 (DBD) 结构类别（例如同源域）和物种。然而，尽管生成了这些大型数据集，但详细的大多数 TF 仍缺乏对 TF-DNA 结合特异性决定因素的了解。疾病突变和 TF 中自然发生的编码变异，尤其是那些在 DBD 中，有可能改变 TF DNA 结合活性。然而，有对 TF-DNA 结合活性的决定因素了解不够准确预测此类编码突变对 DNA 结合活性的影响。这这是一个重要的问题，因为突变或编码变异会损害 TF DNA 结合活性有可能破坏细胞中数千个基因的调节人类基因组。该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合作可能会调节 TF 编码变体对 DNA 结合活性的影响，并确定编码变异损害内在 TF-DNA 的程度识别改变 TF 基因组靶向和基因调控。我们预期我们的结果数据集将揭示 TF-DNA 结合特异性的决定因素，确定哪些因素突变会损害 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。