Abstract
BackgroundAssessing the nucleosome-forming potential of specific DNA sequences is important for understanding complex chromatin organization. Methods for predicting nucleosome positioning include bioinformatics and biophysical approaches. An advantage of bioinformatics methods, which are based on in vivo nucleosome maps, is the use of natural sequences that may contain previously unknown elements involved in nucleosome positioning in vivo. The accuracy of such prediction attempts reflects the genomic coordinate resolution of the nucleosome maps applied. Nucleosome maps are constructed using micrococcal nuclease digestion followed by high-throughput sequencing (MNase-seq). However, as MNase has a strong preference for A/T-rich sequences, MNase-seq may not be appropriate for this purpose. In addition to MNase-seq-based maps, base pair-resolution chemical maps of in vivo nucleosomes from three different species (budding and fission yeasts, and mice) are currently available. However, these chemical maps have yet to be integrated into publicly available computational methods.ResultsWe developed a Bioconductor package (named nuCpos) to demonstrate the superiority of chemical maps in predicting nucleosome positioning. The accuracy of chemical map-based prediction in rotational settings was higher than that of the previously developed MNase-seq-based approach. With our method, predicted nucleosome occupancy reasonably matched in vivo observations and was not affected by A/T nucleotide frequency. Effects of genetic alterations on nucleosome positioning that had been observed in living yeast cells could also be predicted. nuCpos calculates individual histone binding affinity (HBA) scores for given 147-bp sequences to examine their suitability for nucleosome formation. We also established local HBA as a new parameter to predict nucleosome formation, which was calculated for 13 overlapping nucleosomal DNA subsequences. HBA and local HBA scores for various sequences agreed well with previous in vitro and in vivo studies. Furthermore, our results suggest that nucleosomal subsegments that are disfavored in different rotational settings contribute to the defined positioning of nucleosomes.ConclusionsOur results demonstrate that chemical map-based statistical models are beneficial for studying nucleosomal DNA features. Studies employing nuCpos software can enhance understanding of chromatin regulation and the interpretation of genetic alterations and facilitate the design of artificial sequences.
Highlights
Assessing the nucleosome-forming potential of specific DNA sequences is important for understanding complex chromatin organization
Chemical map‐based prediction of nucleosome positioning in yeasts In order to determine whether the bp-resolution chemical maps are suitable for predicting nucleosome positioning, we trained duration hidden Markov model (dHMM) with the nucleosome maps generated with H4-S47C-dependent DNA cleavage
The core dHMM algorithm implemented in our method was not altered from the original algorithm developed for the micrococcal nuclease (MNase)-seq-based method (NuPoP) to clarify the advantages of using the chemical maps
Summary
Assessing the nucleosome-forming potential of specific DNA sequences is important for understanding complex chromatin organization. An advantage of bioinformatics methods, which are based on in vivo nucleosome maps, is the use of natural sequences that may contain previously unknown elements involved in nucleosome positioning in vivo The accuracy of such prediction attempts reflects the genomic coordinate resolution of the nucleosome maps applied. In addition to MNase-seq-based maps, base pair-resolution chemical maps of in vivo nucleosomes from three different species (budding and fission yeasts, and mice) are currently available These chemical maps have yet to be integrated into publicly available computational methods. Nucleosome positioning is combinatorially regulated by trans-acting factors (e.g., transcription factors and chromatin remodeling factors) and by the inherent suitability of the DNA sequence for nucleosome formation [5,6,7] Focusing on the latter requirement, computational methods that assess the nucleosome-forming potential of given DNA sequences have been developed [8]
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