A Model for the Cooperative Binding of Eukaryotic Regulatory Proteins to Nucleosomal Target Sites

Polach, Kevin J.; Widom, Jonathan

doi:10.1006/jmbi.1996.0288

Cited by 245 publications

(240 citation statements)

References 29 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%

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%

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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“…This explains why under equilibrium conditions (at F = 0) the DNA deeply inside the nucleosomes (almost the whole bound DNA!) can be rather easily accessed by proteins [17] but the nucleosome is still highly stable: The line α = 0 can be moved to each position inside the nucleosome if the left and right DNA arms are adsorbed/desorbed in a consistent manner. Beyond that (α > 0) the assisting electrostatics switches off and the nucleosome is suddenly strongly stabilized (by 60 − 70k B T in total!…”

Section: Figmentioning

confidence: 99%

“…Their analysis of the dynamical force spectroscopy measurements revealed an apparent barrier of ∼ 38k B T smeared out over not more than 10 bp. However, there is no experimental indication of such a huge specific barrier -neither from the crystal structure [5] nor from the equilibrium accessibility to nucleosomal DNA [17]. Consequently the question arises if the barrier is really caused by biochemistry of the nucleosome or, as we show below, by its underlying geometry and physics.…”

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confidence: 94%

DNA Spools under Tension

2004

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DNA-spools, structures in which DNA is wrapped and helically coiled onto itself or onto a protein core are ubiquitous in nature. We develop a general theory describing the non-equilibrium behavior of DNA-spools under linear tension. Two puzzling and seemingly unrelated recent experimental findings, the sudden quantized unwrapping of nucleosomes and that of DNA toroidal condensates under tension are theoretically explained and shown to be of the same origin. The study provides new insights into nucleosome and chromatin fiber stability and dynamics. as a means to efficiently pack and transport DNA into cells. In most of these ligand-DNA complexes the geometry and chemistry of the ligand surface enforces the DNA to follow a superhelical wrapping path with one or more tight turns. Remarkably, upon addition of multivalent condensing agents (like in sperm cells) or under high crowding conditions (like in virus capsids or during ψ-condensation) DNA also shows an intrinsic ability to self-organize into large toroidal spools [7].

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“…DNA must dissociate, to some extent, from nucleosomes to allow TFs and RNA polymerase to function. One recent study (Polach and Widom, 1996) models cooperative binding of TFs to nucleosomal target sites. The cooperativity is not due to protein-protein interactions, but rather, the first TF to bind partially dissociates DNA from the nucleosome, making it easier for subsequent TFs to bind.…”

Section: Specific Issues Where Further Investigation Is Neededmentioning

confidence: 99%

“…The model succeeded in quantitatively reproducing the experimental data. Polach and Widom (1996) pointed out that their model suggests a new mechanism of transcriptional regulation. The binding of a particular TF to DNA could be varied by changing the concentration or activity of another TF that binds to a site within the same nucleosome.…”

Section: Specific Issues Where Further Investigation Is Neededmentioning

confidence: 99%

Modeling Transcriptional Control in Gene Networks—Methods, Recent Results, and Future Directions

Smolen

Baxter

Byrne

2000

Bulletin of Mathematical Biology

280

161

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Mathematical models are useful for providing a framework for integrating data and gaining insights into the static and dynamic behavior of complex biological systems such as networks of interacting genes. We review the dynamic behaviors expected from model gene networks incorporating common biochemical motifs, and we compare current methods for modeling genetic networks. A common modeling technique, based on simply modeling genes as ON-OFF switches, is readily implemented and allows rapid numerical simulations. However, this method may predict dynamic solutions that do not correspond to those seen when systems are modeled with a more detailed method using ordinary differential equations. Until now, the majority of gene network modeling studies have focused on determining the types of dynamics that can be generated by common biochemical motifs such as feedback loops or protein oligomerization. For example, these elements can generate multiple stable states for gene product concentrations, state-dependent responses to stimuli, circadian rhythms and other oscillations, and optimal stimulus frequencies for maximal transcription. In the future, as new experimental techniques increase the ease of characterization of genetic networks, qualitative modeling will need to be supplanted by quantitative models for specific systems.

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A Model for the Cooperative Binding of Eukaryotic Regulatory Proteins to Nucleosomal Target Sites

Cited by 245 publications

References 29 publications

Nucleosome packaging and nucleosome positioning of genomic DNA

Nucleosome packaging and nucleosome positioning of genomic DNA

DNA Spools under Tension

Modeling Transcriptional Control in Gene Networks—Methods, Recent Results, and Future Directions

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