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; 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.

项目摘要/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节序列是困难但很重要的 广泛影响学科在内的问题，包括人类遗传学，发展， 和进化。该领域的计算方法通常集中在 转录因子（TF）结合位点。但是，有大量证据 那个核小体远方与TF一起起作用以产生打开 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，移动或驱逐能力 核小组在某些序列上，但不是其他序列，/或更长的范围 诸如填料核小体阵列的序列依赖性之类的机制 对抗障碍。 在这里，我们建议开发识别和描述序列的方法 这些机制的依赖性，可以应用于任何机制 重塑酶。避免其他其他人的复杂效果 因素，这些方法将采用具有纯化成分的生化测定。 然后将对结果数据进行询问，以识别序列特征 与并预测核小体的占用和运动相关的 每种类型的重塑，以及构建的模型，可以检测和评分这些 在任何给定序列中的特征。这些模型可以类似地使用 并与广泛使用的转录因子基序模型结合使用。 如果成功，这些方法可以应用于重塑的许多变体 复合物。结果模型应广泛适用于研究 基因调节，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具有宽度 人类遗传分析的影响和分子遗传的广泛适用性 研究。