Dynamic networks observed in the nucleosome core particles couple the histone globular domains with DNA

Shi, Xiangyan; Prasanna, Chinmayi; Soman, Aghil; Pervushin, Konstantin; Nordenskiöld, Lars

doi:10.1038/s42003-020-01369-3

Cited by 27 publications

(43 citation statements)

References 57 publications

(72 reference statements)

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“…Subsequent MAS NMR studies of mononucleosomes by Shi et al also confirmed these observations ( Shi et al, 2018 ). This discrepancy is most likely due to the type of experiments used (i.e., sidechain vs. backbone correlations), with 13 C MAS NMR experiments holding a slight advantage regarding the detection of slower moving tail sidechains such as those that are close to the DNA interface ( Shi et al, 2018 ; Shi et al, 2020b ). While the detected tail boundary is consistent between arrays and mononucleosomes in MAS NMR experiments, a closer look into the 15 N spin relaxation rates of H3 tails reveals mobility differences ( Zandian et al, 2021 ).…”

Section: Mas Nmr Of Histone Tailsmentioning

confidence: 99%

Emerging Contributions of Solid-State NMR Spectroscopy to Chromatin Structural Biology

Ackermann

Debelouchina

2021

Front. Mol. Biosci.

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The eukaryotic genome is packaged into chromatin, a polymer of DNA and histone proteins that regulates gene expression and the spatial organization of nuclear content. The repetitive character of chromatin is diversified into rich layers of complexity that encompass DNA sequence, histone variants and post-translational modifications. Subtle molecular changes in these variables can often lead to global chromatin rearrangements that dictate entire gene programs with far reaching implications for development and disease. Decades of structural biology advances have revealed the complex relationship between chromatin structure, dynamics, interactions, and gene expression. Here, we focus on the emerging contributions of magic-angle spinning solid-state nuclear magnetic resonance spectroscopy (MAS NMR), a relative newcomer on the chromatin structural biology stage. Unique among structural biology techniques, MAS NMR is ideally suited to provide atomic level information regarding both the rigid and dynamic components of this complex and heterogenous biological polymer. In this review, we highlight the advantages MAS NMR can offer to chromatin structural biologists, discuss sample preparation strategies for structural analysis, summarize recent MAS NMR studies of chromatin structure and dynamics, and close by discussing how MAS NMR can be combined with state-of-the-art chemical biology tools to reconstitute and dissect complex chromatin environments.

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Section: Mas Nmr Of Histone Tailsmentioning

confidence: 99%

Emerging Contributions of Solid-State NMR Spectroscopy to Chromatin Structural Biology

Ackermann

Debelouchina

2021

Front. Mol. Biosci.

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“…First, in order to probe the conformation and dynamics of the H4 tail in the tightly compacted and precipitated arrays, we collected 1 H- 13 C/ 15 N correlation ssNMR spectra in order to detect those AAs in the H4 tail region, which exhibits significant mobility compared with the rigid core region 45 , 46 . By using the known averaged chemical shift values of AAs combined with three-dimensional (3D) solution-state NMR experiments of the histone H4 in a Widom “601” nucleosome core particle 47 , we established the tail peak chemical shift assignments. Interestingly, two peaks, 3.50–62.4 ppm and 3.45–62.8 ppm, were observed in the 1 H− 13 C spectra of the nucleosome arrays containing H4K20me0 or H4K20me3 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…6e and Supplementary fig. 15a, b ), we obtained information about the internal dynamics of the H4 protein backbone at the μs-ms timescale 47 , 49 . In comparison with the H4K20me0 nucleosome array, the globular domain of the H4K20me1 array showed more uniform peak intensities across the protein and reduced relative intensities for several residues primarily residing in the LN and L1 regions and in the adjacent stretch of the α1 and α2 regions (Fig.…”

Section: Resultsmentioning

confidence: 99%

Histone H4 lysine 20 mono-methylation directly facilitates chromatin openness and promotes transcription of housekeeping genes

et al. 2021

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Histone lysine methylations have primarily been linked to selective recruitment of reader or effector proteins that subsequently modify chromatin regions and mediate genome functions. Here, we describe a divergent role for histone H4 lysine 20 mono-methylation (H4K20me1) and demonstrate that it directly facilitates chromatin openness and accessibility by disrupting chromatin folding. Thus, accumulation of H4K20me1 demarcates highly accessible chromatin at genes, and this is maintained throughout the cell cycle. In vitro, H4K20me1-containing nucleosomal arrays with nucleosome repeat lengths (NRL) of 187 and 197 are less compact than unmethylated (H4K20me0) or trimethylated (H4K20me3) arrays. Concordantly, and in contrast to trimethylated and unmethylated tails, solid-state NMR data shows that H4K20 mono-methylation changes the H4 conformational state and leads to more dynamic histone H4-tails. Notably, the increased chromatin accessibility mediated by H4K20me1 facilitates gene expression, particularly of housekeeping genes. Altogether, we show how the methylation state of a single histone H4 residue operates as a focal point in chromatin structure control. While H4K20me1 directly promotes chromatin openness at highly transcribed genes, it also serves as a stepping-stone for H4K20me3-dependent chromatin compaction.

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“…The decrease of long range dynamic correlations throughout the nucleosome observed here, which is a result of both DNA unwrapping and H2A.B substitution altering protein/protein and protein/DNA contacts, may play an additional role in epigenetic regulation. Indeed, allosetric networks within the nucleosome have been observed with solid state NMR experiments (86), and it has been proposed that epigenetic regulators may take advantage of these networks to influence genetic activity (87). Furthermore, it has been shown that allosteric transmission can be exploited to design drugs that bind at sites on the nucleosome surface (88), and that these networks can extend between nucleosomes to alter chromatin fiber dynamics (89).…”

Section: H2ab Reduces Long Range Dynamic Correlationsmentioning

confidence: 99%

Effects of H2A.B incorporation on nucleosome structures and dynamics

Kohestani

Weresczczynski

2020

Preprint

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The H2A.B histone variant is an epigenetic regulator involved in transcriptional upregulation, DNA synthesis, and splicing that functions by replacing the canonical H2A histone in the nucleosome core particle. Introduction of H2A.B results in less compact nucleosome states with increased DNA unwinding and accessibility at the nucleosomal entry and exit sites. Despite being well characterized experimentally, the molecular mechanisms by which H2A.B incorporation alters nucleosome stability and dynamics remain poorly understood. To study the molecular mechanisms of H2A.B, we have performed a series of conventional and enhanced sampling molecular dynamics simulation of H2A.B and canonical H2A containing nucleosomes. Results of conventional simulations show that H2A.B weakens protein/protein and protein/DNA interactions at specific locations throughout the nucleosome. These weakened interactions result in significantly more DNA opening from both the entry and exit sites in enhanced sampling simulations. Furthermore, free energy profiles show that H2A.B containing nucleosomes have significantly broader free wells, and that H2A.B allows for sampling of states with increased DNA breathing, which are shown to be stable on the hundreds of nanoseconds timescale with further conventional simulations. Together, our results show the molecular mechanisms by which H2A.B creates less compacted nucleosome states as a means of increasing genetic accessibility and gene transcription.SIGNIFICANCENature has evolved a plethora of mechanisms for altering the physical and chemical properties of chromatin fibers as a means of controlling gene expression. These epigenetic processes may serve to increase or decrease DNA accessibility, manage the recruitment of remodeling factors, or tune the stability of the nucleosomes that make up chromatin. Here, we have used both conventional and enhanced sampling molecular dynamics simulations to understand how one of these epigenetic mechanisms, the substitution of canonical H2A proteins with the H2A.B variant, exerts its influence on the structures and dynamics of the nucleosome. Results show at the molecular level how this variant alters inter-molecular interactions to increase DNA accessibility as a means of increasing genetic accessibility and gene transcription.

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Dynamic networks observed in the nucleosome core particles couple the histone globular domains with DNA

Cited by 27 publications

References 57 publications

Emerging Contributions of Solid-State NMR Spectroscopy to Chromatin Structural Biology

Emerging Contributions of Solid-State NMR Spectroscopy to Chromatin Structural Biology

Histone H4 lysine 20 mono-methylation directly facilitates chromatin openness and promotes transcription of housekeeping genes

Effects of H2A.B incorporation on nucleosome structures and dynamics

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