Nucleosome positioning: How is it established, and why does it matter?

Radman‐Livaja, Marta; Rando, Oliver J.

doi:10.1016/j.ydbio.2009.06.012

Cited by 268 publications

(268 citation statements)

References 102 publications

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“…Explaining two correlated molecular functions-histone binding and transcriptional regulation-in the same sequence segment may be seen as a chicken-and-egg problem (6)(7)(8)(9). Is transcription factor binding the primary function, which displaces nucleosomes to sequence segments in which transcription is neutral or deleterious?…”

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confidence: 99%

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Fitness landscape for nucleosome positioning

Weghorn

Lässig

2013

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

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Histone-DNA complexes, so-called nucleosomes, are the building blocks of DNA packaging in eukaryotic cells. The histone-binding affinity of a local DNA segment depends on its elastic properties and determines its accessibility within the nucleus, which plays an important role in the regulation of gene expression. Here, we derive a fitness landscape for intergenic DNA segments in yeast as a function of two molecular phenotypes: their elasticity-dependent histone affinity and their coverage with transcription factor binding sites. This landscape reveals substantial selection against nucleosome formation over a wide range of both phenotypes. We use it as the core component of a quantitative evolutionary model for intergenic DNA segments. This model consistently predicts the observed diversity of histone affinities within wild Saccharomyces paradoxus populations, as well as the affinity divergence between neighboring Saccharomyces species. Our analysis establishes histone binding and transcription factor binding as two separable modes of sequence evolution, each of which is a direct target of natural selection.biophysics | nucleosome-depleted regions | evolution of regulation | quantitative traits | inference of selection T he positional organization of nucleosomes in eukaryotic cells is of key importance for the overall chromatin structure and, thus, for the regulation of gene expression (1-3). Nucleosomes form through binding of a histone octamer to a DNA sequence segment of average length 146 base pairs (bp), which wraps around the protein complex (4). Histone-bound DNA segments are interspersed with unbound "linker" segments. Particularly prominent features of this pattern are so-called nucleosome-depleted regions (NDRs). These are extended troughs in occupancy at least ∼100 bp long, primarily located in intergenic DNA. Changes in nucleosome positioning affect the accessibility of local DNA segments for binding interactions with transcription factors and lead to observable changes of gene expression in yeast (3,5).Explaining two correlated molecular functions-histone binding and transcriptional regulation-in the same sequence segment may be seen as a chicken-and-egg problem (6-9). Is transcription factor binding the primary function, which displaces nucleosomes to sequence segments in which transcription is neutral or deleterious? Or, conversely, does nucleosome positioning constrain transcriptional interactions? Here, we address this problem by a quantitative evolutionary analysis of yeast genomes. We infer a fitness landscape for intergenic sequence segments that measures selection on their regulatory interactions and on local nucleosome formation. We capture these functions by two molecular phenotypes, the regulatory binding site content and the histone binding affinity, which reflect distinct biophysical characteristics of a DNA segment. The fitness landscape resulting from our analysis shows substantial selection acting jointly on transcriptional interactions and on nucleosome formation. Specifically, we fi...

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confidence: 99%

“…Several mechanisms are known to influence the local probability of nucleosome formation (8). Histone-affine DNA has a specific nucleotide composition that facilitates superhelical turns around the cylinder-shaped octamer (10,11).…”

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confidence: 99%

Fitness landscape for nucleosome positioning

Weghorn

Lässig

2013

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

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“…The wrapping of the DNA around the histone octamer protein core in the nucleosome impedes the access of transcription factors to the DNA sequence information. Thus, changes of nucleosome positions at promoter and enhancer regions may directly affect gene expression (1)(2)(3)(4). To control nucleosome positions (and with it the access to the associated DNA), a complex chromatin remodeling machinery operates in the eukaryotic cell nucleus.…”

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confidence: 99%

Human ISWI chromatin-remodeling complexes sample nucleosomes via transient binding reactions and become immobilized at active sites

Erdel

Schubert

Marth

et al. 2010

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

109

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Chromatin remodeling complexes can translocate nucleosomes along the DNA in an ATP-dependent manner. Here, we studied autofluorescent protein constructs of the human ISWI family members Snf2H, Snf2L, the catalytically inactive Snf2L+13 splice variant, and the accessory Acf1 subunit in living human and mouse cells by fluorescence microscopy/spectroscopy. Except for Snf2L, which was not detected in the U2OS cell line, the endogenous ISWI proteins were abundant at nuclear concentrations between 0.14 and 0.83 μM. A protein interaction analysis showed the association of multimeric Snf2H and Acf1 into a heterotetramer or higher-order ACF complex. During the G1/2 cell cycle phase, Snf2H and Snf2L displayed average residence times <150 ms in the chromatin-bound state. The comparison of active and inactive Snf2H/Snf2L indicated that an immobilized fraction potentially involved in active chromatin remodeling comprised only 1-3%. This fraction was largely increased at replication foci in S phase or at DNA repair sites. To rationalize these findings we propose that ISWI remodelers operate via a "continuous sampling" mechanism: The propensity of nucleosomes to be translocated is continuously tested in transient binding reactions. Most of these encounters are unproductive and efficient remodeling requires an increased binding affinity to chromatin. Due to the relatively high intranuclear remodeler concentrations cellular response times for repositioning a given nucleosome were calculated to be in the range of tens of seconds to minutes.nucleosome translocation | fluorescence recovery after photobleaching | fluorescence correlation spectroscopy

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“…In Saccharomyces cerevisiae, genomewide mapping of nucleosomes suggests that only a few DNA sequence-based properties such as absence of A/T rich regions, or conversely a high G/C content, have a strong effect on general positioning (discussed in Hughes and Rando 2009;Tillo and Hughes 2009;Radman-Livaja and Rando 2010;Zhang et al 2010), so the dominant mechanism for defining the location of nucleosomes may be statistical positioning (Gkikopoulos et al 2011;Zhang et al 2011). Earlier individual nucleosome mapping approaches in S. cerevisiae at single sites had already shown that barrier effects provided a major positioning effect, with DNA properties and histone-DNA interactions acting to fine tune local accessibility and behaviour (Thoma 1992).…”

Section: In Vivo Positioning As Combination Of Effectsmentioning

confidence: 99%

“…The energetics of these deformations gives rise to sequence specific effects on DNA binding, and many authors have addressed the question of how they are linked with choice of nucleosome position (see Segal and Widom 2009a;Travers et al 2009;Radman-Livaja and Rando 2010;Olson and Zhurkin 2011;Trifonov 2011;Zhurkin 2011;Chua et al 2012).…”

Section: Dna Conformation In the Nucleosomementioning

confidence: 99%

Principles and practice of nucleosome positioningin vitro

Flaus

2011

Frontiers in Life Science

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Nucleosome positioning: How is it established, and why does it matter?

Cited by 268 publications

References 102 publications

Fitness landscape for nucleosome positioning

Fitness landscape for nucleosome positioning

Human ISWI chromatin-remodeling complexes sample nucleosomes via transient binding reactions and become immobilized at active sites

Principles and practice of nucleosome positioningin vitro

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