Regulation of chromatin folding by conformational variations of nucleosome linker DNA

Buckwalter, Jenna; Norouzi, Davood; Harutyunyan, Anna; Zhurkin, Victor B.; Grigoryev, Sergei A.

doi:10.1093/nar/gkx562

Cited by 22 publications

(34 citation statements)

References 70 publications

(122 reference statements)

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“…This observation was made for relatively short 20-and 25-bp linkers observed in yeast [39,40]. Recently, we corroborated this conclusion analyzing nucleosome arrays with 183-and 188-bp NRL [43], typical for higher eukaryotes (L = 36 and 41 bp).…”

Section: Topological Polymorphism Of Chromatin Fiberssupporting

confidence: 82%

Polymorphic 30-nm Chromatin Fiber and Linking Number Paradox. Evidence for the Occurrence of Two Distinct Topoisomers

Norouzi

Zhurkin

2018

Preprint

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We discuss various models of spatial organization of the 30-nm fiber that remains enigmatic despite 40 years of intensive studies. Using computer simulations, we found two topologically different families of the fiber conformations distinguished by the linker length, L: the fibers with L = {10n} and {10n+5} bp have DNA linking numbers per nucleosome DLk » -1.5 and -1.0, respectively. The fibers with DLk » -1.5 were observed earlier, while the topoisomer with DLk » -1.0 is novel. These predictions were confirmed for circular nucleosome arrays with precisely positioned nucleosomes. We suggest that topological polymorphism of chromatin fibers may play a role in the process of transcription, which is known to generate different levels of DNA supercoiling upstream and downstream from RNA polymerase. In particular, the {10n+5} DNA linkers are likely to produce transcriptionally competent chromatin structures. This hypothesis is consistent with available data for several eukaryotes, from yeast to human. We also analyzed two recent studies of chromatin fibers -on the nucleosome crosslinking in vitro, and on radioprobing DNA folding in human cells. In both cases, we show that the novel topoisomer with DLk » -1.0 has to be taken into account to interpret experimental data. This is yet another evidence for occurrence of two distinct fiber topoisomers. Potentially, our findings may reflect a general tendency of chromosomal domains with different levels of transcription to retain topologically different higher-order structures.

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Section: Topological Polymorphism Of Chromatin Fiberssupporting

confidence: 82%

Polymorphic 30-nm Chromatin Fiber and Linking Number Paradox. Evidence for the Occurrence of Two Distinct Topoisomers

Norouzi

Zhurkin

2018

Preprint

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“…The first level of compaction involves wrapping 147 base pairs (bps) of DNA around a histone octamer, forming the nucleosome that repeatedly occurs across the genome. The precise locations of nucleosomes on genomic DNA influence higher-order chromatin structure [1] and regulates diverse cellular processes by controlling local DNA accessibility [2]. Specifically, it is believed that most DNA-binding proteins preferentially bind the unprotected linker DNA between nucleosomes.…”

Section: Introductionmentioning

confidence: 99%

A unified computational framework for modeling genome-wide nucleosome landscape

Finnegan

Song

2018

Phys. Biol.

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Nucleosomes form the fundamental building blocks of eukaryotic chromatin, and previous attempts to understand the principles governing their genome-wide distribution have spurred much interest and debate in biology. In particular, the precise role of DNA sequence in shaping local chromatin structure has been controversial. This paper rigorously quantifies the contribution of hitherto-debated sequence features – including G+C content, 10.5-bp periodicity, and poly(dA:dT) tracts – to three distinct aspects of genome-wide nucleosome landscape: occupancy, translational positioning and rotational positioning. Our computational framework simultaneously learns nucleosome number and nucleosome-positioning energy from genome-wide nucleosome maps. In contrast to other previous studies, our model can predict both in-vitro and in-vivo nucleosome maps in S. cerevisiae. We find that although G+C content is the primary determinant of MNase-derived nucleosome occupancy, MNase digestion biases may substantially influence this GC dependence. By contrast, poly(dA:dT) tracts are seen to deter nucleosome formation, regardless of the experimental method used. We further show that the 10.5-bp nucleotide periodicity facilitates rotational but not translational positioning. Applying our method to in-vivo nucleosome maps demonstrates that, for a subset of genes, the regularly-spaced nucleosome arrays observed around transcription start sites can be partially recapitulated by DNA sequence alone. Finally, in-vivo nucleosome occupancy derived from MNase-seq experiments around transcription termination sites can be mostly explained by the genomic sequence. Implications of these results and potential extensions of the proposed computational framework are discussed.

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“…For chromatin modeling, especially at small and intermediate scales, approaches that rely on basic physical interactions for the description of electrostatics and solvation are of uttermost importance. The other indisputably essential ingredient is the mechanical connection; for example, the presence of high-curvature AT-rich segments (A-tracts) in linker DNA is known to influence nucleosome interaction and alter chromatin folding (Buckwalter et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Chromatin Compaction Multiscale Modeling: A Complex Synergy Between Theory, Simulation, and Experiment

Bendandi

Dante

Zia

et al. 2020

Front. Mol. Biosci.

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Understanding the mechanisms that trigger chromatin compaction, its patterns, and the factors they depend on, is a fundamental and still open question in Biology. Chromatin compacts and reinforces DNA and is a stable but dynamic structure, to make DNA accessible to proteins. In recent years, computational advances have provided larger amounts of data and have made large-scale simulations more viable. Experimental techniques for the extraction and reconstitution of chromatin fibers have improved, reinvigorating theoretical and experimental interest in the topic and stimulating debate on points previously considered as certainties regarding chromatin. A great assortment of approaches has emerged, from all-atom single-nucleosome or oligonucleosome simulations to various degrees of coarse graining, to polymer models, to fractal-like structures and purely topological models. Different fiber-start patterns have been studied in theory and experiment, as well as different linker DNA lengths. DNA is a highly charged macromolecule, making ionic and electrostatic interactions extremely important for chromatin topology and dynamics. Indeed, the repercussions of varying ionic concentration have been extensively examined at the computational level, using all-atom, coarse-grained, and continuum techniques. The presence of high-curvature AT-rich segments in DNA can cause conformational variations, attesting to the fact that the role of DNA is both structural and electrostatic. There have been some tentative attempts to describe the force fields governing chromatin conformational changes and the energy landscapes of these transitions, but the intricacy of the system has hampered reaching a consensus. The study of chromatin conformations is an intrinsically multiscale topic, influenced by a wide range of biological and physical interactions, spanning from the atomic to the chromosome level. Therefore, powerful modeling techniques and carefully planned experiments are required for an overview of the most relevant phenomena and interactions. The topic provides fertile ground for interdisciplinary studies featuring a synergy between theoretical and experimental scientists from different fields and the cross-validation of respective results, with a multi-scale perspective. Here, we summarize some of the most representative approaches, and focus on the importance of electrostatics and solvation, often overlooked aspects of chromatin modeling.

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Regulation of chromatin folding by conformational variations of nucleosome linker DNA

Cited by 22 publications

References 70 publications

Polymorphic 30-nm Chromatin Fiber and Linking Number Paradox. Evidence for the Occurrence of Two Distinct Topoisomers

Polymorphic 30-nm Chromatin Fiber and Linking Number Paradox. Evidence for the Occurrence of Two Distinct Topoisomers

A unified computational framework for modeling genome-wide nucleosome landscape

Chromatin Compaction Multiscale Modeling: A Complex Synergy Between Theory, Simulation, and Experiment

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