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      Distinct Modes of Regulation by Chromatin Encoded through Nucleosome Positioning Signals

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          The detailed positions of nucleosomes profoundly impact gene regulation and are partly encoded by the genomic DNA sequence. However, less is known about the functional consequences of this encoding. Here, we address this question using a genome-wide map of ∼380,000 yeast nucleosomes that we sequenced in their entirety. Utilizing the high resolution of our map, we refine our understanding of how nucleosome organizations are encoded by the DNA sequence and demonstrate that the genomic sequence is highly predictive of the in vivo nucleosome organization, even across new nucleosome-bound sequences that we isolated from fly and human. We find that Poly(dA:dT) tracts are an important component of these nucleosome positioning signals and that their nucleosome-disfavoring action results in large nucleosome depletion over them and over their flanking regions and enhances the accessibility of transcription factors to their cognate sites. Our results suggest that the yeast genome may utilize these nucleosome positioning signals to regulate gene expression with different transcriptional noise and activation kinetics and DNA replication with different origin efficiency. These distinct functions may be achieved by encoding both relatively closed (nucleosome-covered) chromatin organizations over some factor binding sites, where factors must compete with nucleosomes for DNA access, and relatively open (nucleosome-depleted) organizations over other factor sites, where factors bind without competition.

          Author Summary

          The detailed positions of nucleosomes along genomes have critical roles in transcriptional regulation. Consequently, it is important to understand the principles that govern the organization of nucleosomes in vivo and the functional consequences of this organization. Here we report on progress in identifying the functional consequences of nucleosome organization, in understanding the way in which nucleosome organization is encoded in the DNA, and in linking the two, by suggesting that distinct transcriptional behaviors are encoded through the genome's intrinsic nucleosome organization. Our results thus provide insight on the broader question of understanding how transcriptional programs are encoded in the DNA sequence. These new insights were enabled by individually sequencing ∼380,000 nucleosomes from yeast in their entirety. Using this map, we refine our previous model for predicting nucleosome positions and demonstrate that our new model predicts nucleosome organizations in yeast with high accuracy and that its nucleosome positioning signals are predictive across eukaryotes. We show that the yeast genome may utilize these nucleosome positioning signals to encode regions with both relatively open (nucleosome-depleted) chromatin organizations and relatively closed (nucleosome-covered) chromatin organizations and that this encoding can partly explain aspects of transcription factor binding, gene expression, transcriptional noise, and DNA replication.

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          Most cited references 59

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          Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.

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            Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise.

            A major goal of biology is to provide a quantitative description of cellular behaviour. This task, however, has been hampered by the difficulty in measuring protein abundances and their variation. Here we present a strategy that pairs high-throughput flow cytometry and a library of GFP-tagged yeast strains to monitor rapidly and precisely protein levels at single-cell resolution. Bulk protein abundance measurements of >2,500 proteins in rich and minimal media provide a detailed view of the cellular response to these conditions, and capture many changes not observed by DNA microarray analyses. Our single-cell data argue that noise in protein expression is dominated by the stochastic production/destruction of messenger RNAs. Beyond this global trend, there are dramatic protein-specific differences in noise that are strongly correlated with a protein's mode of transcription and its function. For example, proteins that respond to environmental changes are noisy whereas those involved in protein synthesis are quiet. Thus, these studies reveal a remarkable structure to biological noise and suggest that protein noise levels have been selected to reflect the costs and potential benefits of this variation.
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              A genomic code for nucleosome positioning.

              Eukaryotic genomes are packaged into nucleosome particles that occlude the DNA from interacting with most DNA binding proteins. Nucleosomes have higher affinity for particular DNA sequences, reflecting the ability of the sequence to bend sharply, as required by the nucleosome structure. However, it is not known whether these sequence preferences have a significant influence on nucleosome position in vivo, and thus regulate the access of other proteins to DNA. Here we isolated nucleosome-bound sequences at high resolution from yeast and used these sequences in a new computational approach to construct and validate experimentally a nucleosome-DNA interaction model, and to predict the genome-wide organization of nucleosomes. Our results demonstrate that genomes encode an intrinsic nucleosome organization and that this intrinsic organization can explain approximately 50% of the in vivo nucleosome positions. This nucleosome positioning code may facilitate specific chromosome functions including transcription factor binding, transcription initiation, and even remodelling of the nucleosomes themselves.

                Author and article information

                Role: Editor
                PLoS Comput Biol
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                November 2008
                November 2008
                7 November 2008
                : 4
                : 11
                [1 ]Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel
                [2 ]Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois, United States of America
                [3 ]Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
                Duke University, United States of America
                Author notes

                Conceived and designed the experiments: YF NK YFM IKM E. Sharon YL JW E. Segal. Performed the experiments: YF NK YFM IKM E. Sharon YL JW E. Segal. Analyzed the data: YF NK YFM IKM E. Sharon YL JW E. Segal. Contributed reagents/materials/analysis tools: YF NK YFM IKM E. Sharon YL JW E. Segal. Wrote the paper: YF NK YFM IKM E. Sharon YL JW E. Segal.

                Field et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 25
                Research Article
                Computational Biology/Genomics
                Computational Biology/Transcriptional Regulation
                Genetics and Genomics/Bioinformatics
                Genetics and Genomics/Epigenetics

                Quantitative & Systems biology


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