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

• 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
• 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

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.

项目摘要 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细胞生物学中深入研究的主题。 染色体生物学迄今为止，大多数研究都集中在TF上，以了解它们如何识别其结合 核小体中的基序然而，很少有工作研究了它们的结合伴侣核小体的作用。 DNA在相互作用中核小体DNA序列显示出众所周知的~10-bp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）。WW二聚体倾向于发生在 核小体DNA弯曲成面向组蛋白核心的小沟的位点，而SS二聚体 通常位于核小体DNA弯曲成面向核心的大沟的位点。 在结构上，来自组蛋白的保守“链轮”精氨酸残基插入到小沟弯曲位点 （次要-GBS），其中富集WW二核苷酸。因为短的A/T延伸有狭窄的小沟， 在带负电荷的DNA骨架和带正电荷的DNA骨架之间存在有利的相互作用， 精氨酸。最近，我们发现具有相反模式（抗WW/SS模式）的核小体， 在真核生物基因组中广泛存在。抗WW/SS核小体倾向于具有SS（而不是WW） 在小-GBS处的二核苷酸，其被认为与精氨酸残基具有减弱的相互作用。 然而，目前还不清楚具有反WW/SS模式的核小体是否确实具有更不利的功能。 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。在目标1中，我们将 现有的基因组数据来阐明TF结合基因组上核小体耗尽区域的序列基础 网站.在目标2中，我们将检查和比较WW/SS中DNA片段的组蛋白-DNA接触 核小体和反WW/SS核小体。在项目结束时，我们 应该已经阐明了抗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的机制见解。