Nucleosome-free DNA regions differentially affect distant communication in chromatin

Nizovtseva, Ekaterina V.; Clauvelin, Nicolas; Todolli, Stefjord; Polikanov, Yury S.; Kulaeva, Olga I.; Wengrzynek, Scott; Olson, Wilma K.; Studitsky, Vasily M.

doi:10.1093/nar/gkw1240

Cited by 30 publications

(36 citation statements)

References 51 publications

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“…The computations capture the enhanced communication found on constructs with intact nucleosomes compared to tailless nucleosomes ( i.e. , nucleosomes with all tail charges respectively present or absent) [17] and the relative levels of communication on arrays of nucleosomes that carry only the charges on the tails of histones H2A and H2B or histones H3 and H4 [18]. Here we describe the relative deformabilities of the modeled constructs in terms of the global force-constant matrices extracted from the pairwise interactions of nucleosomes in the different simulations (Figure 5).…”

Section: Resultsmentioning

confidence: 99%

“…Here we use a Debye length λ D = 0.83 nm to account for the divalent buffer solutions used in reference experiments [17, 18] and a charge reduction factor ξ = 0.15 for DNA consistent with the ionic composition and double-helical structure [25]. The charge per DNA base pair is set to −2 e so that each reduced point charge in the coarse-grained model is −0.9 e .…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies of enhancer-promoter interactions on well-defined nucleosome arrays offer a new biochemical and biophysical perspective on chromatin structure and deformation [16–18]. The presence of nucleosomes facilitates distant communication between transcriptional proteins bound at the ends of DNA chains [16].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the communication between regulatory proteins, measured in terms of the level of RNA transcripts, is more pronounced on chains containing intact nucleosomes compared to those in which the positively charged N-terminal tails of the histone proteins are removed [17]. Selective excision of the tails from histones H3 and H4 has a greater effect on the biochemical signal than the loss of tails from histones H2A and H2B [18]. …”

Section: Introductionmentioning

confidence: 99%

“…These fine structural details arise naturally through the representation of DNA as a sequence of base pairs rather than as a series of rigid-helical segments or beads of the sort employed in earlier work [13–15, 20]. Simulations of looping performed with the mesoscale model capture the enhancement in long-range communication between regulatory proteins detected experimentally on nucleosome arrays compared to bare DNA and account successfully for the variation in communication levels with the numbers and composition of histones [17, 18]. The correspondence between predicted and observed looping propensities lends credence to the model and to the molecular insights gleaned from the computed structures.…”

Section: Introductionmentioning

confidence: 99%

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Nucleosome positioning and composition modulate in silico chromatin flexibility

Clauvelin

Kulaeva

et al. 2015

J. Phys.: Condens. Matter

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The dynamic organization of chromatin plays an essential role in the regulation of gene expression and in other fundamental cellular processes. The underlying physical basis of these activities lies in the sequential positioning, chemical composition, and intermolecular interactions of the nucleosomes—the familiar assemblies of ~ 150 DNA base pairs and eight histone proteins—found on chromatin fibers. Here we introduce a mesoscale model of short nucleosomal arrays and a computational framework that make it possible to incorporate detailed structural features of DNA and histones in simulations of short chromatin constructs. We explore the effects of nucleosome positioning and the presence or absence of cationic N-terminal histone tails on the ‘local’ inter-nucleosomal interactions and the global deformations of the simulated chains. The correspondence between the predicted and observed effects of nucleosome composition and numbers on the long-range communication between the ends of designed nucleosome arrays lends credence to the model and to the molecular insights gleaned from the simulated structures. We also extract effective nucleosome-nucleosome potentials from the simulations and implement the potentials in a larger-scale computational treatment of regularly repeating chromatin fibers. Our results reveal a remarkable effect of nucleosome spacing on chromatin flexibility, with small changes in DNA linker length significantly altering the interactions of nucleosomes and the dimensions of the fiber as a whole. In addition, we find that these changes in nucleosome positioning influence the statistical properties of long chromatin constructs. That is, simulated chromatin fibers with the same number of nucleosomes exhibit polymeric behaviors ranging from Gaussian to worm-like, depending upon nucleosome spacing. These findings suggest that the physical and mechanical properties of chromatin can span a wide range of behaviors, depending on nucleosome positioning, and that care must be taken in the choice of models used to interpret the experimental properties of long chromatin fibers.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nucleosome positioning and composition modulate in silico chromatin flexibility

Clauvelin

Kulaeva

et al. 2015

J. Phys.: Condens. Matter

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Mechanisms of Enhancer Action

Nizovtseva

Studitsky

2019

Encyclopedia of Life Sciences

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Genomic studies have revealed a large number of distantly acting regulatory DNA regions (enhancers) activating transcription both in bacteria and in eukaryotes. Enhancers contain multiple specific binding sites for activator proteins that can locally disturb chromatin structure after binding to DNA and activate transcription initiated from enhancer targets (promoters) localised at variable distances from the enhancer. Typically, interactions between enhancer‐ and promoter‐bound proteins involve chromatin looping of intervening stretches of DNA organised in chromatin. These dynamic regulatory chromatin loops of different size and stability operate both in bacteria and in higher organisms where they form extensive and complex three‐dimensional networks that largely define gene expression patterns and identity of eukaryotic cells. Misalignment of these networks results in development of numerous human diseases including cancer. Key Concepts Enhancers are regulatory DNA sequences that regulate transcription both in bacteria and in higher organisms. Enhancers are activated after binding of activator proteins to their specific binding sites localised within the enhancers. Enhancers activate their targets (promoters) over variable distances. An enhancer can work on multiple promoters and a promoter can be activated by multiple enhancers. As a result, there is a dynamic regulatory network formed by regulatory chromatin loops of different size and stability. Promoter activation involves interaction between proteins bound at the enhancers and promoters. Enhancer–promoter interaction is accompanied by looping of intervening chromatin. Gene activation involves a conformational change in promoter‐bound proteins or their covalent modification.

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Epigenetic‐based therapy for colorectal cancer: Prospect and involved mechanisms

Rezapour

Hosseinzadeh

Marofi

et al. 2019

Journal Cellular Physiology

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Epigenetic modifications are heritable variations in gene expression not encoded by the DNA sequence. According to reports, a large number of studies have been performed to characterize epigenetic modification during normal development and also in cancer. Epigenetics can be regarded more widely to contain all of the changes in expression of genes that make by adjusted interactions between the regulatory portions of DNA or messenger RNAs that lead to indirect variation in the DNA sequence. In the last decade, epigenetic modification importance in colorectal cancer (CRC) pathogenesis was demonstrated powerfully. Although developments in CRC therapy have been made in the last years, much work is required as it remains the second leading cause of cancer death. Nowadays, epigenetic programs and genetic change have pivotal roles in the CRC incidence as well as progression. While our knowledge about epigenetic mechanism in CRC is not comprehensive, selective histone modifications and resultant chromatin conformation together with DNA methylation most likely regulate CRC pathogenesis that involved genes expression. Undoubtedly, the advanced understanding of epigenetic-based gene expression regulation in the CRC is essential to make epigenetic drugs for CRC therapy. The major aim of this review is to deliver a summary of valuable results that represent evidence of principle for epigeneticbased therapeutic approaches employment in CRC with a focus on the advantages of epigenetic-based therapy in the inhibition of the CRC metastasis and proliferation.

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Nucleosome-free DNA regions differentially affect distant communication in chromatin

Cited by 30 publications

References 51 publications

Nucleosome positioning and composition modulate in silico chromatin flexibility

Nucleosome positioning and composition modulate in silico chromatin flexibility

Mechanisms of Enhancer Action

Epigenetic‐based therapy for colorectal cancer: Prospect and involved mechanisms

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