Abstract
Genome wide maps of nucleosome occupancy in yeast have recently been produced through deep sequencing of nuclease-protected DNA. These maps have been obtained from both crosslinked and uncrosslinked chromatin in vivo, and from chromatin assembled from genomic DNA and nucleosomes in vitro. Here, we analyze these maps in combination with existing ChIP-chip data, and with new ChIP-qPCR experiments reported here. We show that the apparent nucleosome density in crosslinked chromatin, when compared to uncrosslinked chromatin, is preferentially increased at transcription factor (TF) binding sites, suggesting a strategy for mapping generic transcription factor binding sites that would not require immunoprecipitation of a particular factor. We also confirm previous conclusions that the intrinsic, sequence dependent binding of nucleosomes helps determine the localization of TF binding sites. However, we find that the association between low nucleosome occupancy and TF binding is typically greater if occupancy at a site is averaged over a 600bp window, rather than using the occupancy at the binding site itself. We have also incorporated intrinsic nucleosome binding occupancies as weights in a computational model for TF binding, and by this measure as well we find better prediction if the high resolution nucleosome occupancy data is averaged over 600bp. We suggest that the intrinsic DNA binding specificity of nucleosomes plays a role in TF binding site selection not so much through the specification of precise nucleosome positions that permit or occlude binding, but rather through the creation of low occupancy regions that can accommodate competition from TFs through rearrangement of nucleosomes.
Highlights
Genomic DNA is largely covered in proteins, mostly in the form of nucleosomes
That nucleosomes and transcription factor (TF) do, compete on a genomicwide scale was substantiated several years ago by chromatin immunoprecipitation microarray experiments (ChIP-chip), which determined the distribution of histones along the yeast genome. [1,2,3] These studies revealed an under-representation of nucleosomes in promoter regions, relative to transcribed regions
How nucleosomes come to occupy particular sites and thereby compete with sequence specific transcription factors is a central problem in developing a systems-level understanding of gene regulation
Summary
Genomic DNA is largely covered in proteins, mostly in the form of nucleosomes. Much of the remainder consists of chromatinassociated proteins, including enzymes that modify histones or DNA, or catalyze the rearrangement of nucleosomes, and sequence specific DNA binding proteins (transcription factors) that mediate the activation or repression of genes. A deep understanding of gene regulation requires an understanding of how each of these cooperate and compete for access to genomic DNA. That nucleosomes and TFs do, compete on a genomicwide scale was substantiated several years ago by chromatin immunoprecipitation microarray experiments (ChIP-chip), which determined the distribution of histones along the yeast genome. [1,2,3] These studies revealed an under-representation of nucleosomes in promoter regions, relative to transcribed regions. TFs are under-represented in transcribed regions and enriched in promoter regions. Nucleosome occupancy differs among promoters and these differences correlate with the probability of TF binding. [4]
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