Measuring and describing nucleosome remodeler sequence preferences

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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.