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Regulation of the nucleosome repeat length in vivo by the DNA sequence, protein concentrations and long-range interactions.

ABSTRACT: The nucleosome repeat length (NRL) is an integral chromatin property important for its biological functions. Recent experiments revealed several conflicting trends of the NRL dependence on the concentrations of histones and other architectural chromatin proteins, both in vitro and in vivo, but a systematic theoretical description of NRL as a function of DNA sequence and epigenetic determinants is currently lacking. To address this problem, we have performed an integrative biophysical and bioinformatics analysis in species ranging from yeast to frog to mouse where NRL was studied as a function of various parameters. We show that in simple eukaryotes such as yeast, a lower limit for the NRL value exists, determined by internucleosome interactions and remodeler action. For higher eukaryotes, also the upper limit exists since NRL is an increasing but saturating function of the linker histone concentration. Counterintuitively, smaller H1 variants or non-histone architectural proteins can initiate larger effects on the NRL due to entropic reasons. Furthermore, we demonstrate that different regimes of the NRL dependence on histone concentrations exist depending on whether DNA sequence-specific effects dominate over boundary effects or vice versa. We consider several classes of genomic regions with apparently different regimes of the NRL variation. As one extreme, our analysis reveals that the period of oscillations of the nucleosome density around bound RNA polymerase coincides with the period of oscillations of positioning sites of the corresponding DNA sequence. At another extreme, we show that although mouse major satellite repeats intrinsically encode well-defined nucleosome preferences, they have no unique nucleosome arrangement and can undergo a switch between two distinct types of nucleosome positioning.

SUBMITTER: Beshnova DA

PROVIDER: S-EPMC4081033 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Regulation of the nucleosome repeat length in vivo by the DNA sequence, protein concentrations and long-range interactions.

Beshnova Daria A DA Cherstvy Andrey G AG Vainshtein Yevhen Y Teif Vladimir B VB

PLoS computational biology 20140703 7

The nucleosome repeat length (NRL) is an integral chromatin property important for its biological functions. Recent experiments revealed several conflicting trends of the NRL dependence on the concentrations of histones and other architectural chromatin proteins, both in vitro and in vivo, but a systematic theoretical description of NRL as a function of DNA sequence and epigenetic determinants is currently lacking. To address this problem, we have performed an integrative biophysical and bioinfo ...[more]

PMID: 24992723

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Project description:BackgroundKnowing the three-dimensional (3D) structure of the chromatin is important for obtaining a complete picture of the regulatory landscape. Changes in the 3D structure have been implicated in diseases. While there exist approaches that attempt to predict the long-range chromatin interactions, they focus only on interactions between specific genomic regions - the promoters and enhancers, neglecting other possibilities, for instance, the so-called structural interactions involving intervening chromatin.ResultsWe present a method that can be trained on 5C data using the genetic sequence of the candidate loci to predict potential genome-wide interaction partners of a particular locus of interest. We have built locus-specific support vector machine (SVM)-based predictors using the oligomer distance histograms (ODH) representation. The method shows good performance with a mean test AUC (area under the receiver operating characteristic (ROC) curve) of 0.7 or higher for various regions across cell lines GM12878, K562 and HeLa-S3. In cases where any locus did not have sufficient candidate interaction partners for model training, we employed multitask learning to share knowledge between models of different loci. In this scenario, across the three cell lines, the method attained an average performance increase of 0.09 in the AUC. Performance evaluation of the models trained on 5C data regarding prediction on an independent high-resolution Hi-C dataset (which is a rather hard problem) shows 0.56 AUC, on average. Additionally, we have developed new, intuitive visualization methods that enable interpretation of sequence signals that contributed towards prediction of locus-specific interaction partners. The analysis of these sequence signals suggests a potential general role of short tandem repeat sequences in genome organization.ConclusionsWe demonstrated how our approach can 1) provide insights into sequence features of locus-specific interaction partners, and 2) also identify their cell-line specificity. That our models deem short tandem repeat sequences as discriminative for prediction of potential interaction partners, suggests that they could play a larger role in genome organization. Thus, our approach can (a) be beneficial to broadly understand, at the sequence-level, chromatin interactions and higher-order structures like (meta-) topologically associating domains (TADs); (b) study regions omitted from existing prediction approaches using various information sources (e.g., epigenetic information); and

Dataset Information

Regulation of the nucleosome repeat length in vivo by the DNA sequence, protein concentrations and long-range interactions.

Publications

Regulation of the nucleosome repeat length in vivo by the DNA sequence, protein concentrations and long-range interactions.

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