DNA Shape Dominates Sequence Affinity in Nucleosome Formation

Freeman, Gordon S.; Lequieu, Joshua; Hinckley, Daniel M.; Whitmer, Jonathan K.; Pablo, Juan J. de

doi:10.1103/physrevlett.113.168101

Cited by 97 publications

(132 citation statements)

References 28 publications

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“…To examine nucleosome repositioning, we rely on a coarsegrained model of the nucleosome that combines the "3 Site Per Nucleotide" (3SPN) model of DNA with the "AtomicInteraction-based Coarse-Grained" (AICG) model of proteins (47,48). By combining detailed, fully validated models of DNA (49) and proteins (50), the 3SPN-AICG combination has been demonstrated to accurately reproduce experimental measurements of both the tension-dependent and sequence-dependent binding free energies of nucleosome formation without introducing adjustable parameters (48).…”

Section: Resultsmentioning

confidence: 99%

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In silico evidence for sequence-dependent nucleosome sliding

Lequieu

Schwartz

Pablo

2017

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

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107

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Nucleosomes represent the basic building block of chromatin and provide an important mechanism by which cellular processes are controlled. The locations of nucleosomes across the genome are not random but instead depend on both the underlying DNA sequence and the dynamic action of other proteins within the nucleus. These processes are central to cellular function, and the molecular details of the interplay between DNA sequence and nucleosome dynamics remain poorly understood. In this work, we investigate this interplay in detail by relying on a molecular model, which permits development of a comprehensive picture of the underlying free energy surfaces and the corresponding dynamics of nucleosome repositioning. The mechanism of nucleosome repositioning is shown to be strongly linked to DNA sequence and directly related to the binding energy of a given DNA sequence to the histone core. It is also demonstrated that chromatin remodelers can override DNA-sequence preferences by exerting torque, and the histone H4 tail is then identified as a key component by which DNA-sequence, histone modifications, and chromatin remodelers could in fact be coupled.nucleosome repositioning | chromatin dynamics | molecular simulation | advanced sampling techniques T he basic building block of eukaryotic chromatin is the nucleosome, a DNA-protein complex containing 147 bp of DNA wrapped around a disk-like protein complex known as the histone octamer (1). Since nucleosomal DNA is inaccessible to other DNA-binding proteins, such as transcription factors and polymerases (2-4), the locations of nucleosomes represent an important mechanism by which cellular processes are controlled. Notably, nucleosome positions are dynamic, with changes in transcription levels, cellular state, and environmental factors resulting in different packagings of chromatin (5, 6). Proper packaging of genomic DNA is critical to cellular function, and a wide range of human diseases have been associated with defects in chromatin structure (7,8). Understanding the molecular factors that control the locations of nucleosomes, and how they are dynamically modulated, therefore represents a central goal of molecular biology and biophysics.It is now appreciated that the DNA sequence itself represents a key factor that governs the locations of nucleosomes. Different DNA sequences exhibit different affinities for the histone proteins, and as such, they form nucleosomes with probabilities that can differ by several orders of magnitude (9, 10). The dependence of nucleosome locations on DNA sequence originates from subtle differences in the intrinsic shape and flexibility of a specific DNA sequence, which lead to favorable electrostatic interactions between the DNA backbone and residues on the histone surface (11). In fact, this pronounced dependence on DNA sequence has led several authors to propose that a genetic code exists (12, 13) where the positions of 50% of nucleosomes in vivo are dictated by DNA sequence alone. Such a view, however, is not without controversy (14, 15),...

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Section: Resultsmentioning

confidence: 99%

“…The order parameter S R has been used previously to quantify the positioning preferences of different DNA sequences to the histone proteins (47).…”

Section: Methodsmentioning

confidence: 99%

In silico evidence for sequence-dependent nucleosome sliding

Lequieu

Schwartz

Pablo

2017

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

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107

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“…7,36 We note this kind of simple treatment of the direct protein-DNA interaction has already been applied successfully to study protein DNA interactions in a wide range of biological systems, [37][38][39] including some studies of nucleosomes. 40,41 We introduce two modifications to the original AWSEM force field presented in Ref. 8 in order to improve modeling the chemical complexity of histone proteins.…”

Section: Coarse-grained Protein-dna Modelmentioning

confidence: 99%

Exploring the Free Energy Landscape of Nucleosomes

Zhang¹,

Zheng²,

et al. 2016

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The nucleosome is the fundamental unit for packaging the genome. A detailed molecular picture for its conformational dynamics is crucial for understanding transcription and gene regulation. We investigate the disassembly of single nucleosomes using a predictive coarse-grained protein DNA model with transferable force fields. This model quantitatively describes the thermodynamic stability of both the histone core complex and the nucleosome and predicts rates of transient nucleosome opening that match experimental measurements. Quantitative characterization of the free-energy landscapes reveals the mechanism of nucleosome unfolding in which DNA unwinding and histone protein disassembly are coupled. The interfaces between H2A-H2B dimers and the (H3-H4)2 tetramer are first lost when the nucleosome opens releasing a large fraction but not all of its bound DNA. For the short strands studied in single molecule experiments, the DNA unwinds asymmetrically from the histone proteins, with only one of its two ends preferentially exposed. The detailed molecular mechanism revealed in this work provides a structural basis for interpreting experimental studies of nucleosome unfolding.

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“…The so-called “intrinsic curvature” of DNA, which emerges over circa 100 base pairs, depends strongly on DNA sequence [11–13] and is purported to play a role in biological processes such as nucleosome positioning [14–17]. Likewise, certain sequences such as poly(A) tracts introduce local bends in DNA [18–21], again at very short length scales.…”

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confidence: 99%

Sequence-Dependent Persistence Length of Long DNA

et al. 2017

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Using a high-throughput genome mapping approach, we have obtained circa 50 million measurements of the extension of internal human DNA segments in a 41 nm × 41 nm nanochannel. The underlying DNA sequences, obtained by mapping to the reference human genome, are 2.5 to 393 kilobase pairs long and contain % GC contents between 32.5% and 60%. Using Odijk’s theory for a channel-confined wormlike chain, these data reveal that the DNA persistence length increases by almost 20% as the % GC content increases. The increased persistence length is rationalized by a model, containing no adjustable parameters, that treats the DNA as a statistical terpolymer with a sequence-dependent intrinsic persistence length and a sequence-independent electrostatic persistence length.

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DNA Shape Dominates Sequence Affinity in Nucleosome Formation

Cited by 97 publications

References 28 publications

In silico evidence for sequence-dependent nucleosome sliding

In silico evidence for sequence-dependent nucleosome sliding

Exploring the Free Energy Landscape of Nucleosomes

Sequence-Dependent Persistence Length of Long DNA

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