Measuring and describing nucleosome remodeler sequence preferences

测量和描述核小体重塑序列偏好

• 批准号: 10526907
• 负责人: Timothy Hughes
• 金额: $ 26.73万
• 依托单位: UNIVERSITY OF TORONTO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526907
• 关键词: Area; Binding; Binding Sites; Biochemical; Biochemical Genetics; Biological Assay; Biological Process; Capsid Proteins; Cells; Characteristics; Chromatin; Complex; Computational algorithm; Computer Analysis; Cues; DNA; DNA Binding; DNA Binding Domain; DNA Sequence; Data; Dependence; Development; Discipline; Elements; Enhancers; Enzymes; Evolution; Family; Gene Expression Regulation; Genes; Genetic Research; Genetic Transcription; Genome; Goals; Histones; Human; Human Genetics; Human Genome; Individual; Knowledge; Location; Measures; Methodology; Methods; Modeling; Modification; Molecular Genetics; Movement; Multienzyme Complexes; Nucleosomes; Pilot Projects; Positioning Attribute; Protein Isoforms; Proteins; Regulation; Regulatory Element; Scanning; Site; Specificity; System; Testing; Validation; Variant; Work; experimental study; genetic analysis; improved; prediction algorithm; predictive modeling; preference; reconstitution; recruit; response; transcription factor; virtual

PROJECT SUMMARY/ABSTRACT Hughes - “Measuring and describing nucleosome remodeler sequence preferences” Determining how cells interpret regulatory sequence is a difficult but important problem that broadly impacts disciplines including human genetics, development, and evolution. Computational approaches in this area are usually focused on transcription factor (TF) binding sites. There is substantial evidence, however, that nucleosome remodelers, which work together with TFs to generate open chromatin at regulatory sites, also possess some level of sequence specificity. This specificity could involve direct sequence recognition, ability to move or evict nucleosomes over some sequences but not others, and/or longer-range mechanisms such as sequence dependence of packing nucleosome arrays against a barrier. Here, we propose to develop methods to identify and describe the sequence dependence of each of these mechanisms, which can be applied to any remodeling enzyme. To avoid the complex and confounding effects of other factors, the methods will employ biochemical assays with purified components. The resulting data will then be interrogated to identify sequence features that correlate with and predict nucleosome occupancy and movement in response to each type of remodeler, and models constructed that can detect and score these features within any given sequence. These models can be used analogously to and in conjunction with widely used transcription factor motif models. If successful, these methods could be applied to the many variants of remodeling complexes. The resulting models should be widely applicable in the study of gene regulation, analogous to transcription factor DNA binding motifs. Development and validation of this method could therefore have widespread impact in human genetic analysis and broad applicability in molecular genetic research.

项目概要/摘要 休斯 - “测量和描述核小体重塑序列 “偏好” 确定细胞如何解释调控序列是一项困难但重要的工作 广泛影响人类遗传学、发育、 该领域的计算方法通常侧重于。 然而，有大量证据表明，转录因子（TF）结合位点。 核小体重塑者与转录因子一起产生开放的 调节位点的染色质也具有一定程度的序列特异性。 这种特异性可能涉及直接序列识别、移动或驱逐的能力 核小体在某些序列上，但不在其他序列上，和/或更长范围 包装核小体阵列的序列依赖性等机制 对抗障碍。 在这里，我们建议开发识别和描述序列的方法 这些机制中的每一个的依赖性，可以应用于任何 避免其他酶的复杂和混淆作用。 因素，这些方法将采用纯化成分的生化测定。 然后将询问所得数据以识别序列特征 关联并预测核小体的占据和运动 每种类型的重塑者，以及构建的可以检测和评分这些的模型 任何给定序列中的特征都可以类似地使用。 并与广泛使用的转录因子基序模型相结合。 如果成功，这些方法可以应用于多种改造 由此产生的模型应该广泛适用于研究。 基因调控，类似于转录因子 DNA 结合基序。 因此，该方法的开发和验证可能会得到广泛的应用 对人类遗传分析的影响和分子遗传学的广泛适用性 研究。