Abstract
BackgroundIn eukaryotic organisms, DNA is packaged into chromatin structure, where most of DNA is wrapped into nucleosomes. DNA compaction and nucleosome positioning have clear functional implications, since they modulate the accessibility of genomic regions to regulatory proteins. Despite the intensive research effort focused in this area, the rules defining nucleosome positioning and the location of DNA regulatory regions still remain elusive.ResultsNaked (histone-free) and nucleosomal DNA from yeast were digested by microccocal nuclease (MNase) and sequenced genome-wide. MNase cutting preferences were determined for both naked and nucleosomal DNAs. Integration of their sequencing profiles with DNA conformational descriptors derived from atomistic molecular dynamic simulations enabled us to extract the physical properties of DNA on a genomic scale and to correlate them with chromatin structure and gene regulation. The local structure of DNA around regulatory regions was found to be unusually flexible and to display a unique pattern of nucleosome positioning. Ab initio physical descriptors derived from molecular dynamics were used to develop a computational method that accurately predicts nucleosome enriched and depleted regions.ConclusionsOur experimental and computational analyses jointly demonstrate a clear correlation between sequence-dependent physical properties of naked DNA and regulatory signals in the chromatin structure. These results demonstrate that nucleosome positioning around TSS (Transcription Start Site) and TTS (Transcription Termination Site) (at least in yeast) is strongly dependent on DNA physical properties, which can define a basal regulatory mechanism of gene expression.
Highlights
In eukaryotic organisms, DNA is packaged into chromatin structure, where most of DNA is wrapped into nucleosomes
microccocal nuclease (MNase) displayed quite strong sequence preferences in naked DNA (Table 1) that could not be ascribed to experimental artifacts, given the fact that control experiments where DNA was fragmented by sonication did not show any marked variation in genome-wide profile (Additional File 1: Figure S1)
We found a good agreement in the preferred cutting sites between naked and nucleosomal DNAs (Table 2). This suggests that tetramer signals that are directing the first MNase cut in chromatin are intrinsic to naked DNA
Summary
DNA is packaged into chromatin structure, where most of DNA is wrapped into nucleosomes. DNA compaction and nucleosome positioning have clear functional implications, since they modulate the accessibility of genomic regions to regulatory proteins. Genomic studies mostly provide one-dimensional information encoded in DNA, but we cannot ignore the fact that in eukaryotic organisms, DNA is packaged into chromatin structure, where DNA folds to a global compaction of at least 104 [1]. Genome homeostatic histone concentration ensures most of DNA to be wrapped into chromatin structure and function was obtained from genome-wide analysis of chromatin DNase I degradation profiles, which revealed a cross-link between DNase I hypersensitive sites and regulatory regions [7,8,9]. To which extent nucleosome positioning in vivo is really dictated by the DNA sequence is still an issue of strong discussion [25,26,27]
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