Mechanism of Protein Access to Specific DNA Sequences in Chromatin: A Dynamic Equilibrium Model for Gene Regulation

Polach, Kevin J.; Widom, Jonathan

doi:10.1006/jmbi.1995.0606

Cited by 626 publications

(718 citation statements)

References 52 publications

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“…In the context of our site exposure model for the mechanism of regulatory protein binding to nucleosomal target sites (15,32), biases in average positioning of mobile nucleosomes substantially affect the average concentration of the regulatable (accessible) state of nucleosomes. Biases in positioning may also contribute to the stability of higher order chromatin folding (24), potentially at multiple hierarchical levels in the structure.…”

Section: Discussionmentioning

confidence: 99%

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Nucleosome packaging and nucleosome positioning of genomic DNA

Lowary

Widom

1997

Proc. Natl. Acad. Sci. U.S.A.

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118

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The goals of this study were to assess the extent to which bulk genomic DNA sequences contribute to their own packaging in nucleosomes and to reveal the relationship between nucleosome packaging and positioning. Using a competitive nucleosome reconstitution assay, we found that at least 95% of bulk DNA sequences have an affinity for histone octamer in nucleosomes that is similar to that of randomly synthesized DNA; they contribute little to their own packaging at the level of individual nucleosomes. An equation was developed that relates the measured free energy to the fractional occupancy of specific nucleosome positions. Evidently, the bulk of eukaryotic genomic DNA is also not evolved or constrained for significant sequence-directed nucleosome positioning at the level of individual nucleosomes. Implications for gene regulation in vivo are discussed.DNA in nucleosomes is tightly bent in comparison to its persistence length, a length scale of DNA stiffness (1). Substantial mechanical work must be done against the bending stiffness to package DNA in nucleosomes; this mechanical work is done at the expense of the favorable free energy of histone-DNA interactions and subtracts from the net thermodynamic stability of the particles. The free energies involved are surprisingly large. Taking the persistence length of DNA to be 50 nm and assuming that DNA in a nucleosome is uniformly bent in a circular trajectory at a radius of curvature of 4.4 nm leads to an estimated free energy cost (1) for bending DNA in a nucleosome of Ϸ75 kcal⅐mol Ϫ1 . Indeed, because of previous estimates such as this, it was once considered remarkable that nucleosome exist at all. Analogous problems exist for DNA twist.The discovery that certain DNA sequences are naturally bent (2) suggested that eukaryotic genomic DNA sequences might be evolved or constrained to facilitate their packaging in nucleosomes (3, 4). Moreover, one might anticipate the existence of a relationship between the free energy of nucleosomal packaging and the phenomenon of nucleosome positioning (such an equation is developed in the present study), suggesting the possibility that nucleosome positioning signals may be encoded in genomic DNA. This idea is interesting in part because of the relationship between nucleosome positioning and gene regulation (5).Results from several studies support the hypothesis that genomes are evolved to facilitate their own packaging. (i) Analyses of DNA fragments present in isolated nucleosome core particles, chromatosomes, and dinucleosomes reveal nonrandom periodic distributions of certain dinucleotides and longer sequences, with particular relative phases (see ref. 6 and references therein). The results suggest that such sequences facilitate the bending of DNA that is necessary for nucleosome formation and that the bending may be produced by an anisotropic flexibility of the AϩT-rich and GϩC-rich regions.(ii) Shrader and Crothers (7, 8) designed sequences de novo that obeyed these rules. The designed sequences were found to bind his...

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Section: Discussionmentioning

confidence: 99%

“…PCRs were pooled and purified as described (15,16). Our final yield of DNA was 132 g, corresponding to Ϸ82 copies each of 5 ϫ 10 12 different molecules.…”

Section: Methodsmentioning

confidence: 99%

Nucleosome packaging and nucleosome positioning of genomic DNA

Lowary

Widom

1997

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

118

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“…Measured values of equilibrium accessibility and corresponding results from the model of nucleosome energetics. 67 The inset shows a schematic of the coordinate system used to define the burial depth of the binding site of interest. wrapped in nucleosomes, the preferred locations of nucleosomes may strongly impact the DNA accessibility and function of critical DNA regions.…”

Section: Figurementioning

confidence: 99%

Biological consequences of tightly bent DNA: The other life of a macromolecular celebrity

et al. 2006

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The mechanical properties of DNA play a critical role in many biological functions. For example, DNA packing in viruses involves confining the viral genome in a volume (the viral capsid) with dimensions that are comparable to the DNA persistence length. Similarly, eukaryotic DNA is packed in DNA-protein complexes (nucleosomes) in which DNA is tightly bent around protein spools. DNA is also tightly bent by many proteins that regulate transcription, resulting in a variation in gene expression that is amenable to quantitative analysis. In these cases, DNA loops are formed with lengths that are comparable to or smaller than the DNA persistence length. The aim of this review is to describe the physical forces associated with tightly bent DNA in all of these settings and to explore the biological consequences of such bending, as increasingly accessible by single-molecule techniques.

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“…During processes like replication or transcription, the entire length of nucleosomal DNA is exposed (although not necessarily all at once) to the polymerases. Processes of 'site exposure' more rapid than the characteristic time for nucleosome sliding has been presented as an attractive model for the initial binding of regulatory proteins to nucleosomal target sites [31,143]. The observed LRC between bending sites might play a role in the dynamical DNA peeling off the histone octamer surface as well as in the mechanisms by which the polymerases progress through nucleosomes.…”

Section: What Mechanisms Underly Lrc In Genome Sequences?mentioning

confidence: 99%

Wavelet Analysis of DNA Bending Profiles reveals Structural Constraints on the Evolution of Genomic Sequences

Audit

Vaillant

Arnéodo

et al. 2004

Journal of Biological Physics

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Abstract. Analyses of genomic DNA sequences have shown in previous works that base pairs are correlated at large distances with scale-invariant statistical properties. We show in the present study that these correlations between nucleotides (letters) result in fact from long-range correlations (LRC) between sequence-dependent DNA structural elements (words) involved in the packaging of DNA in chromatin. Using the wavelet transform technique, we perform a comparative analysis of the DNA text and of the corresponding bending profiles generated with curvature tables based on nucleosome positioning data. This exploration through the optics of the so-called 'wavelet transform microscope' reveals a characteristic scale of 100 − 200 bp that separates two regimes of different LRC. We focus here on the existence of LRC in the small-scale regime ( 200 bp). Analysis of genomes in the three kingdoms reveals that this regime is specifically associated to the presence of nucleosomes. Indeed, small scale LRC are observed in eukaryotic genomes and to a less extent in archaeal genomes, in contrast with their absence in eubacterial genomes. Similarly, this regime is observed in eukaryotic but not in bacterial viral DNA genomes. There is one exception for genomes of Poxviruses, the only animal DNA viruses that do not replicate in the cell nucleus and do not present small scale LRC. Furthermore, no small scale LRC are detected in the genomes of all examined RNA viruses, with one exception in the case of retroviruses. Altogether, these results strongly suggest that small-scale LRC are a signature of the nucleosomal structure. Finally, we discuss possible interpretations of these small-scale LRC in terms of the mechanisms that govern the positioning, the stability and the dynamics of the nucleosomes along the DNA chain. This paper is maily devoted to a pedagogical presentation of the theoretical concepts and physical methods which are well suited to perform a statistical analysis of genomic sequences. We review the results obtained with the so-called waveletbased multifractal analysis when investigating the DNA sequences of various organisms in the three kingdoms. Some of these results have been announced in B. Audit et al. [1,2].

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Mechanism of Protein Access to Specific DNA Sequences in Chromatin: A Dynamic Equilibrium Model for Gene Regulation

Cited by 626 publications

References 52 publications

Nucleosome packaging and nucleosome positioning of genomic DNA

Nucleosome packaging and nucleosome positioning of genomic DNA

Biological consequences of tightly bent DNA: The other life of a macromolecular celebrity

Wavelet Analysis of DNA Bending Profiles reveals Structural Constraints on the Evolution of Genomic Sequences

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