The Molecular Evolution of Nucleosome Positioning Through Sequence-Dependent Deformation of the DNA Polymer

School of Biological and Medical Sciences, Rochester Institute of Technology, Rochester, NY, USA.
Journal of biomolecular Structure & Dynamics (Impact Factor: 2.92). 06/2010; 27(6):765-80. DOI: 10.1080/07391102.2010.10508584
Source: PubMed


The computational prediction of nucleosome positioning from DNA sequence now allows for in silico investigation of the molecular evolution of biophysical properties of the DNA molecule responsible for primary chromatin organization in the genome. To discern what signal components driving nucleosome positioning in the yeast genome are potentially targeted by natural selection, we compare the performance of various models predictive of nucleosome positioning within the context of a simple statistical test, the repositioned mutation test. We demonstrate that while nucleosome occupancy is driven largely by translational exclusion in response to AT content, there is also a strong signature of evolutionary conservation of regular patterns within nucleosomal DNA sequence related to the structural organization of the nucleosome core (e.g., 10-bp dinucleotide periodicity). We also use computer simulations to investigate hypothetical coding and regulatory constraints on the ability of sequence properties affecting nucleosome formation to adaptively evolve. Our results demonstrate that natural selection may act independently on different DNA sequence properties responsible for local chromatin organization. Furthermore, at least with respect to the deformation energy of the DNA molecule in the nucleosome, the presence of the genetic code has greatly restricted the ability of sequences to evolve the dynamic nucleosome organization typically observed in promoter regions.

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    • "It has also been found that, near the 5' end of genes, a uniform 165 bp spacing of nucleosomes (18 bp linker) extends to as many as nine nucleosomes [5-8,13-15]. Importantly, many of these features are evolutionary conserved [7,16]. "
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    ABSTRACT: Divergence of transcription factor binding sites is considered to be an important source of regulatory evolution. The associations between transcription factor binding sites and phenotypic diversity have been investigated in many model organisms. However, the understanding of other factors that contribute to it is still limited. Recent studies have elucidated the effect of chromatin structure on molecular evolution of genomic DNA. Though the profound impact of nucleosome positions on gene regulation has been reported, their influence on transcriptional evolution is still less explored. With the availability of genome-wide nucleosome map in yeast species, it is thus desirable to investigate their impact on transcription factor binding site evolution. Here, we present a comprehensive analysis of the role of nucleosome positioning in the evolution of transcription factor binding sites. We compared the transcription factor binding site frequency in nucleosome occupied regions and nucleosome depleted regions in promoters of old (orthologs among Saccharomycetaceae) and young (Saccharomyces specific) genes; and in duplicate gene pairs. We demonstrated that nucleosome occupied regions accommodate greater binding site variations than nucleosome depleted regions in young genes and in duplicate genes. This finding was confirmed by measuring the difference in evolutionary rates of binding sites in sensu stricto yeasts at nucleosome occupied regions and nucleosome depleted regions. The binding sites at nucleosome occupied regions exhibited a consistently higher evolution rate than those at nucleosome depleted regions, corroborating the difference in the selection constraints at the two regions. Finally, through site-directed mutagenesis experiment, we found that binding site gain or loss events at nucleosome depleted regions may cause more expression differences than those in nucleosome occupied regions. Our study indicates the existence of different selection constraint on binding sites at nucleosome occupied regions than at the nucleosome depleted regions. We found that the binding sites have a different rate of evolution at nucleosome occupied and depleted regions. Finally, using transcription factor binding site-directed mutagenesis experiment, we confirmed the difference in the impact of binding site changes on expression at these regions. Thus, our work demonstrates the importance of composite analysis of chromatin and transcriptional evolution.
    BMC Evolutionary Biology 05/2011; 11(1):150. DOI:10.1186/1471-2148-11-150 · 3.37 Impact Factor
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    • "Firstly, that only a subset of the cell nucleosome positions may be predictable and secondly, that the sequence constraints of nucleosomal DNA, if any, appear to be very weak. Even recent studies that have attempted to establish a clearer connection between the underlying sequence and the positioning of nucleosomes in the light of new experimental evidence [11,17-20] have not attempted to provide a concise framework for what drives nucleosome positioning on DNA, other than the well-reported, ubiquitous dinucleotide periodicities. Overall, the observations made by various research groups using both experimental and theoretical approaches imply that there are few regions in the genome in which the nucleosomal landscape is consistent across the cellular population, and that the majority of the nucleosomes are stochastically positioned. "
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    ABSTRACT: Recent advances in the field of high-throughput genomics have rendered possible the performance of genome-scale studies to define the nucleosomal landscapes of eukaryote genomes. Such analyses are aimed towards providing a better understanding of the process of nucleosome positioning, for which several models have been suggested. Nevertheless, questions regarding the sequence constraints of nucleosomal DNA and how they may have been shaped through evolution remain open. In this paper, we analyze in detail different experimental nucleosome datasets with the aim of providing a hypothesis for the emergence of nucleosome-forming sequences. We compared the complete sets of nucleosome positions for the budding yeast (Saccharomyces cerevisiae) as defined in the output of two independent experiments with the use of two different experimental techniques. We found that < 10% of the experimentally defined nucleosome positions were consistently positioned in both datasets. This subset of well-positioned nucleosomes, when compared with the bulk, was shown to have particular properties at both sequence and structural levels. Consistently positioned nucleosomes were also shown to occur preferentially in pairs of dinucleosomes, and to be surprisingly less conserved compared with their adjacent nucleosome-free linkers. Our findings may be combined into a hypothesis for the emergence of a weak nucleosome-positioning code. According to this hypothesis, consistent nucleosomes may be partly guided by nearby nucleosome-free regions through statistical positioning. Once established, a set of well-positioned consistent nucleosomes may impose secondary constraints that further shape the structure of the underlying DNA. We were able to capture these constraints through the application of a recently introduced structural property that is related to the symmetry of DNA curvature. Furthermore, we found that both consistently positioned nucleosomes and their adjacent nucleosome-free regions show an increased tendency towards conservation of this structural feature.
    Epigenetics & Chromatin 11/2010; 3(1):20. DOI:10.1186/1756-8935-3-20 · 5.33 Impact Factor
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    • "deformation energy) to quantitatively define the nucleosome formation potential of any given sequence (Tolstorukov et al., 2007, 2008). Evolutionary functional conservation of nucleosome organization was then determined by comparing the actual local difference in deformation energy of DNA polymer between two homologous sequences to a null distribution of deformation energy differences generated under an assumption of neutral evolution (Babbitt et al., 2010). We found that selection against spurious motifs is considerably relaxed in TFs associated with functionally conserved chromatin states (Fig. 1A; t = 7.7, p b 0.001 n = 178) and that this group also exhibits much shorter motifs (Fig. 1B; t = 4.1, p b 0.001, n = 178). "
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    ABSTRACT: The spurious (or nonfunctional) binding of transcription factors (TF) to the wrong locations on DNA presents a formidable challenge to genomes given the relatively low ceiling for sequence complexity within the short lengths of most binding motifs. The high potential for the occurrence of random motifs and subsequent nonfunctional binding of many transcription factors should theoretically lead to natural selection against the occurrence of spurious motif throughout the genome. However, because of the active role that chromatin can influence over eukaryotic gene regulation, it may also be expected that many supposed spurious binding sites could escape purifying selection if (A) they simply occur in regions of high nucleosome occupancy or (B) their surrounding chromatin was dynamically involved in their identity and function. We compared nucleosome occupancy and the presence/absence of functionally conserved chromatin context to the strength of selection against spurious binding of various TF binding motifs in Saccharomyces yeast. While we find no direct relationship with nucleosome occupancy, we find strong evidence that transcription factors spatially associated with evolutionarily conserved chromatin states are under relaxed selection against accidental binding. Transcription factors (with/without) a conserved chromatin context were found to occur on average, (87.7%/49.3%) of their expected frequencies. Functional binding motifs with conserved chromatin contexts were also significantly shorter in length and more often clustered. These results indicate a role of chromatin context dependency in relaxing selection against spurious binding in nearly half of all TF binding motifs throughout the yeast genome.
    Gene 10/2010; 466(1-2):43-8. DOI:10.1016/j.gene.2010.07.002 · 2.14 Impact Factor
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