Measuring and describing nucleosome remodeler sequence preferences

项目总结/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个困难但重要的问题。 这个问题广泛影响了包括人类遗传学，发展， 和进化。这一领域的计算方法通常集中在 转录因子（TF）结合位点。然而，有大量证据表明， 核小体重塑，与TF一起工作， 在调控位点的染色质，也具有一定水平的序列特异性。 这种特异性可能涉及直接序列识别，移动或驱逐的能力， 在某些序列上的核小体，而不是其他序列，和/或更长的范围 包装核小体阵列的序列依赖性等机制 一个障碍。 在这里，我们建议开发方法来识别和描述序列 这些机制中的每一个的依赖性，可以应用于任何 重塑酶为了避免复杂和混淆的影响，其他 由于这些因素，这些方法将使用纯化组分的生物化学测定。 然后将询问所得数据以鉴定序列特征， 与核小体占据和运动相关并预测核小体占据和运动， 每种类型的重塑者，以及构建的模型，可以检测和评分这些 任何给定序列中的特征。这些模型可以类似地用于 并结合广泛使用的转录因子基序模型。 如果成功，这些方法可以应用于重塑的许多变体， 配合物由此产生的模型应广泛适用于研究 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具有广泛的 在人类遗传分析中影响和在分子遗传学中的广泛适用性 research.

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.