Uncovering the role of a new DNA sequence pattern in nucleosome-protein interactions

揭示新的 DNA 序列模式在核小体-蛋白质相互作用中的作用

基本信息

批准号：
10628145
负责人：
Feng Cui
金额：
$ 44.4万
依托单位：
ROCHESTER INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-05 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10628145
关键词：
Address Adenine Affinity Amino Acid Sequence Area Arginine Base Sequence Binding Binding Sites Biology Charge Chromatin Chromosomes Cytosine DNA DNA Binding Domain DNA Sequence DNA-Binding Proteins Dinucleoside Phosphates Docking Electrostatics Exhibits Genome Genomics Grant Guanine Histones Length Machine Learning Major Groove Mammalian Cell Methods Minor Groove Modernization Molecular Biology Nucleosomes Pattern Periodicals Phase Play Positioning Attribute Proteins Protocols documentation Publishing Research Role Site Statistical Data Interpretation Stretching System Testing Thymine Time Vertebral column Work dimer flexibility genomic data genomic signature in silico inorganic phosphate insight machine learning method machine learning model machine learning prediction molecular dynamics novel statistical and machine learning transcription factor

项目摘要

Project Summary Uncovering the role of a new DNA sequence pattern in nucleosome–protein interactions How transcription factors (TFs) interact with nucleosomes has been a subject under intensive research in chromosome biology. Most studies so far are focused on TFs to understand how they recognize their binding motifs in a nucleosome. Very few work, however, has investigated the role of their binding partner, nucleosomal DNA, in the interaction. Nucleosomal DNA sequences exhibit a well-known ~10-bp periodic pattern of WW/SS dinucleotides (where W is adenine or thymine and S is guanine or cytosine). WW dimers tend to occur at the sites where nucleosomal DNA bends into minor grooves facing toward the histones core, whereas SS dimers are often positioned at the sites where nucleosomal DNA bends into major grooves facing toward the core. Structurally, conserved ‘sprocket’ arginine residues from histones insert into the minor-groove bending sites (minor-GBS) where WW dinucleotides are enriched. Because short A/T stretches have narrowed minor grooves, there is a favorable interaction between the negatively charged DNA backbone and the positively charged arginine residues. Recently, we found that nucleosomes with an opposite pattern, anti-WW/SS pattern, are widespread across eukaryotic genomes. Anti-WW/SS nucleosomes tend to have SS (instead of WW) dinucleotides at the minor-GBS, which are thought to have a weakened interaction with the arginine residues. However, it remains unclear whether nucleosomes with the anti-WW/SS pattern indeed have less favorable histone-DNA contacts and how this unusual pattern influences TF binding in chromatin. In Aim 1, we will leverage existing genomic data to elucidate the sequence basis for nucleosome depleted regions over TF-bound genomic sites. In Aim 2, we will examine and compare histone-DNA contacts for fragments of DNA in WW/SS nucleosomes and anti-WW/SS nucleosomes using molecular dynamics simulation. At the end of the project, we should have clarified the role of the anti-WW/SS pattern in the histone-DNA and nucleosome-TF interactions as compared to the common WW/SS pattern, which will provide novel mechanistic insights into these interactions.

项目概要揭示新的 DNA 序列模式在核小体-蛋白质相互作用中的作用转录因子（TF）如何与核小体相互作用一直是深入研究的课题迄今为止，大多数研究都集中在 TF 上，以了解它们如何识别其结合。然而，很少有工作研究它们的结合伙伴核小体的作用。 DNA，在相互作用中，核小体 DNA 序列表现出众所周知的 WW/SS 周期性模式。二核苷酸（其中 W 是腺嘌呤或胸腺嘧啶，S 是鸟嘌呤或胞嘧啶）。核小体 DNA 弯曲成面向组蛋白核心的小凹槽的位点，而 SS 二聚体通常位于核小体 DNA 弯曲成面向核心的大凹槽的位置。在结构上，来自组蛋白的保守“链轮”精氨酸残基插入小沟弯曲位点（小-GBS），其中 WW 二核苷酸富集，因为短 A/T 延伸使小凹槽变窄，带负电荷的 DNA 骨架与带正电荷的 DNA 骨架之间存在有利的相互作用最近，我们发现具有相反模式（抗 WW/SS 模式）的核小体。广泛存在于真核生物基因组中。抗 WW/SS 核小体往往具有 SS（而不是 WW）。次要 GBS 上的二核苷酸被认为与精氨酸残基的相互作用减弱。然而，目前尚不清楚具有抗 WW/SS 模式的核小体是否确实具有较差的有利性在目标 1 中，我们将利用组蛋白-DNA 接触以及这种不寻常的模式如何影响染色质中的 TF 结合。现有基因组数据阐明 TF 结合基因组上核小体耗尽区域的序列基础在目标 2 中，我们将检查并比较 WW/SS 中 DNA 片段的组蛋白-DNA 接触。使用分子动力学模拟研究核小体和抗 WW/SS 核小体。应该阐明了抗 WW/SS 模式在组蛋白-DNA 和核小体-TF 相互作用中的作用与常见的 WW/SS 模式相比，这将为这些相互作用提供新颖的机制见解。