Conformational and Interaction Landscape of Histone H4 Tails in Nucleosomes Probed by Paramagnetic NMR Spectroscopy

Sun, Wenjun; Lebedenko, Olga O.; Salguero, Nicole Gonzalez; Shannon, Matthew D.; Zandian, Mohamad; Poirier, Michael G.; Skrynnikov, Nikolai R.; Jaroniec, Christopher P.

doi:10.1021/jacs.3c10340

Cited by 5 publications

(1 citation statement)

References 61 publications

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“…The 4-microsecond MD simulations performed later (47) gave essentially the same result – namely, the H4 N-tails don’t go beyond the limits established by the x-ray structure (29). Finally, the very recent NMR study (48) accompanied by 5-microsecond MD simulations has also localized the H4 tails in the DNA region from SHL ±1 to SHL ±2.5.…”

Section: Resultsmentioning

confidence: 98%

Histone N-tails modulate sequence-specific positioning of nucleosomes

Nikitina,

Guiblet,

Cui

et al. 2023

Preprint

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The precise mechanisms governing sequence-dependent positioning of nucleosomes on DNA remain unknown in detail. Existing algorithms, taking into account the sequence-dependent deformability of DNA and its interactions with the histone globular domains, predict rotational setting of only 65% of human nucleosomes mappedin vivo. To uncover novel factors responsible for the nucleosome positioning, we analyzed potential involvement of the histone N-tails in this process. To this aim, we reconstituted the H2A/H4 N-tailless nucleosomes on human BRCA1 DNA (∼100 kb) and compared their positions and sequences with those of the wild-type nucleosomes. In the case of H2A tailless nucleosomes, the AT content of DNA sequences is changed locally at superhelical location (SHL) ±4, while maintaining the same rotational setting as their wild-type counterparts. Conversely, the H4 tailless nucleosomes display widespread changes of the AT content near SHL ±1 and SHL ±2, where the H4 N-tails interact with DNA. Furthermore, a substantial number of H4 tailless nucleosomes exhibit rotational setting opposite to that of the wild-type nucleosomes. Thus, our findings strongly suggest that the histone N-tails are operative in selection of nucleosome positions, which may have wide-ranging implications for epigenetic modulation of chromatin states.

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Section: Resultsmentioning

confidence: 98%

Histone N-tails modulate sequence-specific positioning of nucleosomes

Nikitina,

Guiblet,

Cui

et al. 2023

Preprint

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Molecular dynamics simulations of nucleosomes are coming of age

Fedulova,

Armeev,

Romanova

et al. 2024

WIREs Comput Mol Sci

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Understanding the function of eukaryotic genomes, including the human genome, is undoubtedly one of the major scientific challenges of the 21st century. The cornerstone of eukaryotic genome organization is nucleosomes—elementary building blocks of chromatin about 10 nm in size that wrap DNA around an octamer of histone proteins. Nucleosomes are integral players in all genomic processes, including transcription, DNA replication and repair. They mediate genome regulation at the epigenetic level, bridging the discrete nature of the genetic information encoded in DNA with the analog physical nature of the intermolecular interactions required to access that information. Due to their relatively large size and dynamic nature, nucleosomes are difficult objects for experimental characterization. Molecular dynamics (MD) simulations have emerged over the years as a useful tool to complement experimental studies. Particularly in recent years, advances in computing power, refinement of MD force fields and codes have opened up new frontiers in terms of simulation timescales and quality for nucleosomes and related systems. It has become possible to elucidate in atomistic detail their functional dynamics modes such as DNA unwrapping and sliding, to characterize the effects of epigenetic modifications, DNA and protein sequence variation on nucleosome structure and stability, to describe the mechanisms governing nucleosome interactions with chromatin‐associated proteins and the formation of supranucleosome structures. In this review, we systematically analyzed all‐atom MD simulation studies of nucleosomes and related structures published since 2018 and discussed their relevance in the context of older studies, experimental data, and related coarse‐grained and multiscale studies.This article is categorized under: Software > Molecular Modeling Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Structure and Mechanism > Computational Biochemistry and Biophysics

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Structural dynamics in chromatin unraveling by pioneer transcription factors

Orsetti,

van Oosten,

Vasarhelyi

et al. 2024

Biophys Rev

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Pioneer transcription factors are proteins with a dual function. First, they regulate transcription by binding to nucleosome-free DNA regulatory elements. Second, they bind to DNA while wrapped around histone proteins in the chromatin and mediate chromatin opening. The molecular mechanisms that connect the two functions are yet to be discovered. In recent years, pioneer factors received increased attention mainly because of their crucial role in promoting cell fate transitions that could be used for regenerative therapies. For example, the three factors required to induce pluripotency in somatic cells, Oct4, Sox2, and Klf4 were classified as pioneer factors and studied extensively. With this increased attention, several structures of complexes between pioneer factors and chromatin structural units (nucleosomes) have been resolved experimentally. Furthermore, experimental and computational approaches have been designed to study two unresolved, key scientific questions: First, do pioneer factors induce directly local opening of nucleosomes and chromatin fibers upon binding? And second, how do the unstructured tails of the histones impact the structural dynamics involved in such conformational transitions? Here we review the current knowledge about transcription factor–induced nucleosome dynamics and the role of the histone tails in this process. We discuss what is needed to bridge the gap between the static views obtained from the experimental structures and the key structural dynamic events in chromatin opening. Finally, we propose that integrating nuclear magnetic resonance spectroscopy with molecular dynamics simulations is a powerful approach to studying pioneer factor–mediated dynamics of nucleosomes and perhaps small chromatin fibers using native DNA sequences.

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Conformational and Interaction Landscape of Histone H4 Tails in Nucleosomes Probed by Paramagnetic NMR Spectroscopy

Cited by 5 publications

References 61 publications

Histone N-tails modulate sequence-specific positioning of nucleosomes

Histone N-tails modulate sequence-specific positioning of nucleosomes

Molecular dynamics simulations of nucleosomes are coming of age

Structural dynamics in chromatin unraveling by pioneer transcription factors

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