Chromatin Unfolding by Epigenetic Modifications Explained by Dramatic Impairment of Internucleosome Interactions: A Multiscale Computational Study

Collepardo-Guevara, Rosana; Portella, Guillem; Vendruscolo, Michele; Frenkel, Daan; Schlick, Tamar; Orozco, Modesto

doi:10.1021/jacs.5b04086

Cited by 152 publications

(199 citation statements)

References 97 publications

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“…The observed asymmetry in LH binding could also be captured and related to the asymmetry of the CTD itself. Our recent multiscale study also reproduced the effects of a common epigenetic modification on global chromatin architecture (28). Most recently, in agreement with cross-linking data, our model has reproduced internucleosome interaction patterns for interphase and metaphase chromatin to suggest a hierarchical looping mechanism for condensed chromatin (29).…”

Section: Mesocale Chromatin Modelsupporting

confidence: 81%

Correlation among DNA Linker Length, Linker Histone Concentration, and Histone Tails in Chromatin

Luque

Ozer

Schlick

2016

Biophysical Journal

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Eukaryotic cells condense their genetic material in the nucleus in the form of chromatin, a macromolecular complex made of DNA and multiple proteins. The structure of chromatin is intimately connected to the regulation of all eukaryotic organisms, from amoebas to humans, but its organization remains largely unknown. The nucleosome repeat length (NRL) and the concentration of linker histones (ρLH) are two structural parameters that vary among cell types and cell cycles; the NRL is the number of DNA basepairs wound around each nucleosome core plus the number of basepairs linking successive nucleosomes. Recent studies have found a linear empirical relationship between the variation of these two properties for different cells, but its underlying mechanism remains elusive. Here we apply our established mesoscale chromatin model to explore the mechanisms responsible for this relationship, by investigating chromatin fibers as a function of NRL and ρLH combinations. We find that a threshold of linker histone concentration triggers the compaction of chromatin into well-formed 30-nm fibers; this critical value increases linearly with NRL, except for long NRLs, where the fibers remain disorganized. Remarkably, the interaction patterns between core histone tails and chromatin elements are highly sensitive to the NRL and ρLH combination, suggesting a molecular mechanism that could have a key role in regulating the structural state of the fibers in the cell. An estimate of the minimized work and volume associated with storage of chromatin fibers in the nucleus further suggests factors that could spontaneously regulate the NRL as a function of linker histone concentration. Both the tail interaction map and DNA packing considerations support the empirical NRL/ρLH relationship and offer a framework to interpret experiments for different chromatin conditions in the cell.

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Section: Mesocale Chromatin Modelsupporting

confidence: 81%

Correlation among DNA Linker Length, Linker Histone Concentration, and Histone Tails in Chromatin

Luque

Ozer

Schlick

2016

Biophysical Journal

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“…Further experimental and modeling studies of nucleosome interactions using high-resolution multiscale computational approaches (2,44) are essential for connecting chromatin's structural and epigenetic states.…”

Section: Discussionmentioning

confidence: 99%

Hierarchical looping of zigzag nucleosome chains in metaphase chromosomes

Grigoryev

Bascom

Buckwalter

et al. 2016

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

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174

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The architecture of higher-order chromatin in eukaryotic cell nuclei is largely unknown. Here, we use electron microscopy-assisted nucleosome interaction capture (EMANIC) cross-linking experiments in combination with mesoscale chromatin modeling of 96-nucleosome arrays to investigate the internal organization of condensed chromatin in interphase cell nuclei and metaphase chromosomes at nucleosomal resolution. The combined data suggest a novel hierarchical looping model for chromatin higher-order folding, similar to rope flaking used in mountain climbing and rappelling. Not only does such packing help to avoid tangling and self-crossing, it also facilitates rope unraveling. Hierarchical looping is characterized by an increased frequency of higher-order internucleosome contacts for metaphase chromosomes compared with chromatin fibers in vitro and interphase chromatin, with preservation of a dominant two-start zigzag organization associated with the 30-nm fiber. Moreover, the strong dependence of looping on linker histone concentration suggests a hierarchical self-association mechanism of relaxed nucleosome zigzag chains rather than longitudinal compaction as seen in 30-nm fibers. Specifically, concentrations lower than one linker histone per nucleosome promote self-associations and formation of these looped networks of zigzag fibers. The combined experimental and modeling evidence for condensed metaphase chromatin as hierarchical loops and bundles of relaxed zigzag nucleosomal chains rather than randomly coiled threads or straight and stiff helical fibers reconciles aspects of other models for higher-order chromatin structure; it constitutes not only an efficient storage form for the genomic material, consistent with other genome-wide chromosome conformation studies that emphasize looping, but also a convenient organization for local DNA unraveling and genome access. chromatin higher-order structure | nucleosome | linker histone | mesoscale modeling | electron microscopy T he physical packaging of megabase pairs of genomic DNA stored as the chromatin fiber in eukaryotic cell nuclei has been one of the great challenges in biology (1). The limited resolution and disparate levels that can be studied by both experimental and modeling studies of chromatin, which exhibits multiple spatial and temporal scales par excellence, make it challenging to present an integrated structural view, from nucleosomes to chromosomes (2). Because all fundamental template-directed processes of DNA depend on chromatin architecture, advances in our understanding of chromatin higher-order organization are needed to help interpret numerous regulatory events from DNA damage repair to epigenetic control.At the primary structural level, the DNA makes ∼1.7 left-superhelical turns around eight core histones to form a nucleosome core. The nucleosome cores are connected by linker DNA to form nucleosome arrays. An X-ray crystal structure of the nucleosome core has been solved at atomic resolution (3), and a short, four-nucleosome array has also been ...

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“…Here we observe a similar trend in the PANS. Further, more detailed investigation of the structure and dynamics of the histone tails in PANS at the fully atomistic level will likely require much longer simulation times (35) than reported here, or/and the use of coarse-grained approaches (79). Comparison with more appropriate experimental observables, beyond those considered in this work, may be needed for a detailed validation of the conformational ensembles representing the histone tails.…”

Section: The Histone Tailsmentioning

confidence: 96%

Partially Assembled Nucleosome Structures at Atomic Detail

Rychkov

Ilatovskiy

Nazarov

et al. 2017

Biophysical Journal

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The evidence is now overwhelming that partially assembled nucleosome states (PANS) are as important as the canonical nucleosome structure for the understanding of how accessibility to genomic DNA is regulated in cells. We use a combination of molecular dynamics simulation and atomic force microscopy to deliver, in atomic detail, structural models of three key PANS: the hexasome (H2A$H2B)$(H3$H4) 2 , the tetrasome (H3$H4) 2 , and the disome (H3$H4). Despite fluctuations of the conformation of the free DNA in these structures, regions of protected DNA in close contact with the histone core remain stable, thus establishing the basis for the understanding of the role of PANS in DNA accessibility regulation. On average, the length of protected DNA in each structure is roughly 18 basepairs per histone protein. Atomistically detailed PANS are used to explain experimental observations; specifically, we discuss interpretation of atomic force microscopy, Fö rster resonance energy transfer, and small-angle x-ray scattering data obtained under conditions when PANS are expected to exist. Further, we suggest an alternative interpretation of a recent genome-wide study of DNA protection in active chromatin of fruit fly, leading to a conclusion that the three PANS are present in actively transcribing regions in a substantial amount. The presence of PANS may not only be a consequence, but also a prerequisite for fast transcription in vivo.

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Chromatin Unfolding by Epigenetic Modifications Explained by Dramatic Impairment of Internucleosome Interactions: A Multiscale Computational Study

Cited by 152 publications

References 97 publications

Correlation among DNA Linker Length, Linker Histone Concentration, and Histone Tails in Chromatin

Correlation among DNA Linker Length, Linker Histone Concentration, and Histone Tails in Chromatin

Hierarchical looping of zigzag nucleosome chains in metaphase chromosomes

Partially Assembled Nucleosome Structures at Atomic Detail

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