Elucidating the Influence of Linker Histone Variants on Chromatosome Dynamics and Energetics

Woods, Dustin C.; Weresczczynski, Jeff

doi:10.1101/660076

Cited by 13 publications

(24 citation statements)

References 101 publications

(121 reference statements)

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“…As shown in Figures 4 and 5, our more compact model requires more diverse sampling of the linker DNA, which was previously shown to be hindered upon on-dyad binding. 75 A compact chromatin fiber with H1 bound on-dyad would be more strained than its off-dyad bound counterpart and easily perturbed upon a reduction in ionic strength, as observed by Garcia-Saez et al…”

Section: Discussionmentioning

confidence: 93%

“…Their work provided strong reinforcement that shifts between these two states are directly associated with a shift in linker histone binding mode, 51 a sentiment which we share. 75 Here, we quantified the effects of linker histones on condensation using various metrics from an atomistic perspective. Furthermore, this work demonstrates that chromatin can experience large conformational transitions in timescales of under a microsecond, which is well under the time it may take to expose nucleosomes for transcription and DNA repair.…”

Section: Discussionmentioning

confidence: 99%

“…Models of compact octa-nucleosome structures were generated through a combination of manual placement and flexible fitting of the 1KX5 nucleosome 79 and H1 linker histone crystal structures 75 into the cryo-EM map by Song et al (see Methods). 22 To quantify the configurations of these complexes, we took advantage of their double-helical like structures and measured the six canonical parameters of rise, twist, roll, tilt, shift, and slide, which are typically associated with DNA basepairs (see Methods for definitions).…”

Section: Linker Histones Stabilize Tetra-nucleosome Repeatsmentioning

confidence: 99%

“…In a previous study, we emphasized the significance of these interactions by demonstrating how the linker histone binding pose, along with how their mere presence, can affect experimental results. 75 Here, we translated these ideas to the context of poly-nucleosomal arrays by plotting the in-and out-of-nucleosomal-plane motions of both linker DNA arms in Figure 4 and Supplementary Figure S7 Figure 5 shows that those effects are more pronounced in poly-nucleosome systems. For example, the α-Entry angle sampling range was reduced by 56.7…”

Section: Greater Poly-nucleosome Architecture Dictates Linker Dna Sammentioning

confidence: 99%

“…74 In a previous study, we used all-atom molecular dynamics (MD) simulations to demonstrate that the linker histone binding mode on nucleosomes can have substantial effects on linker DNA dynamics. 75 Furthermore, we postulated that its presence would have cascading effects on higher order chromatin structures. Indeed, this is highlighted in many of the previously mentioned studies, but none of which provide a mechanism detailing the atomistic dynamics of the chromatin fiber in and out of the presence of H1.…”

Section: Introductionmentioning

confidence: 99%

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The Dynamic Influence of Linker Histone Saturation within the Poly-Nucleosome Array

Woods

iacuteguez-Ropero

Wereszczynski

2020

Preprint

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Linker histones bind to nucleosomes and modify chromatin structure and dynamics as a means of epigenetic regulation. Biophysical studies have shown that chromatin fibers can adopt a plethora of conformations with varying levels of compaction. Linker histone condensation, and its specific binding disposition, has been associated with directly tuning this ensemble of states. However, the atomistic dynamics and quantification of this mechanism remains poorly understood. Here, we present molecular dynamics simulations of octa-nucleosome arrays, based on a cryo-EM structure of the 30-nm chromatin fiber, with and without the globular domains of the H1 linker histone to determine how they influence fiber structures and dynamics. Results show that when bound, linker histones inhibit DNA flexibility and stabilize repeating tetra-nucleosomal units, giving rise to increased chromatin compaction. Furthermore, upon the removal of H1, there is a significant destabilization of this compact structure as the fiber adopts less strained and untwisted states. Interestingly, linker DNA sampling in the octa-nucleosome is exaggerated compared to its mono-nucleosome counterparts, suggesting that chromatin architecture plays a significant role in DNA strain even in the absence of linker histones. Moreover, H1-bound states are shown to have increased stiffness within tetra-nucleosomes, but not between them. This increased stiffness leads to stronger long-range correlations within the fiber, which may result in the propagation of epigenetic signals over longer spatial ranges. These simulations highlight the effects of linker histone binding on the internal dynamics and global structure of poly-nucleosome arrays, while providing physical insight into a mechanism of chromatin compaction.SignificanceLinker histones dynamically bind to DNA in chromatin fibers and serve as epigentic regulators. However, the extent to which they influence the gamut of chromatin architecture is still not well understood. Using molecular dynamics simulations, we studied compact octa-nucleosome arrays with and without the H1 linker histone to better understand the mechanisms dictating the structure of the chromatin fiber. Inclusion of H1 results in stabilization of the compact chromatin structure, while its removal results in a major conformational change towards an untwisted ladder-like state. The increased rigidity and correlations within the H1-bound array suggests that H1-saturated chromatin fibers are better suited to transferring long-range epigentic information.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Linker Histones Stabilize Tetra-nucleosome Repeatsmentioning

confidence: 99%

Section: Greater Poly-nucleosome Architecture Dictates Linker Dna Sammentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Dynamic Influence of Linker Histone Saturation within the Poly-Nucleosome Array

Woods

iacuteguez-Ropero

Wereszczynski

2020

Preprint

Self Cite

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Can aggressive cancers be identified by the “aggressiveness” of their chromatin?

Gurova

2022

BioEssays

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Phenotypic plasticity is a crucial feature of aggressive cancer, providing the means for cancer progression. Stochastic changes in tumor cell transcriptional programs increase the chances of survival under any condition. I hypothesize that unstable chromatin permits stochastic transitions between transcriptional programs in aggressive cancers and supports non‐genetic heterogeneity of tumor cells as a basis for their adaptability. I present a mechanistic model for unstable chromatin which includes destabilized nucleosomes, mobile chromatin fibers and random enhancer‐promoter contacts, resulting in stochastic transcription. I suggest potential markers for “unsettled” chromatin in tumors associated with poor prognosis. Although many of the characteristics of unstable chromatin have been described, they were mostly used to explain changes in the transcription of individual genes. I discuss approaches to evaluate the role of unstable chromatin in non‐genetic tumor cell heterogeneity and suggest using the degree of chromatin instability and transcriptional noise in tumor cells to predict cancer aggressiveness.

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Structure, dynamics, and stability of the globular domain of human linker histone H1.0 and the role of positive charges

et al. 2022

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Linker histone H1 (H1) is an abundant chromatin-binding protein that acts as an epigenetic regulator binding to nucleosomes and altering chromatin structures and dynamics. Nonetheless, the mechanistic details of its function remain poorly understood. Recent work suggest that the number and position of charged side chains on the globular domain (GD) of H1 influence chromatin structure and hence gene repression. Here, we solved the solution structure of the unbound GD of human H1.0, revealing that the structure is almost completely unperturbed by complex formation, except for a loop connecting two antiparallel β-strands. We further quantified the role of the many positive charges of the GD for its structure and conformational stability through the analysis of 11 charge variants. We find that modulating the number of charges has little effect on the structure, but the stability is affected, resulting in a difference in melting temperature of 26 K between GD of net charge +5 versus +13. This result suggests that the large number of positive charges on H1-GDs have evolved for function rather than structure and high stability. The stabilization of the GD upon binding to DNA can thus be expected to have a pronounced electrostatic component, a contribution that is amenable to modulation by posttranslational modifications, especially acetylation and phosphorylation.

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Elucidating the Influence of Linker Histone Variants on Chromatosome Dynamics and Energetics

Cited by 13 publications

References 101 publications

The Dynamic Influence of Linker Histone Saturation within the Poly-Nucleosome Array

The Dynamic Influence of Linker Histone Saturation within the Poly-Nucleosome Array

Can aggressive cancers be identified by the “aggressiveness” of their chromatin?

Structure, dynamics, and stability of the globular domain of human linker histone H1.0 and the role of positive charges

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