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Molecular mechanism of histone variant H2A.B on stability and assembly of nucleosome and chromatin structures.

ABSTRACT: BACKGROUND:H2A.B, the most divergent histone variant of H2A, can significantly modulate nucleosome and chromatin structures. However, the related structural details and the underlying mechanism remain elusive to date. In this work, we built atomic models of the H2A.B-containing nucleosome core particle (NCP), chromatosome, and chromatin fiber. Multiscale modeling including all-atom molecular dynamics and coarse-grained simulations were then carried out for these systems. RESULTS:It is found that sequence differences at the C-terminal tail, the docking domain, and the L2 loop, between H2A.B and H2A are directly responsible for the DNA unwrapping in the H2A.B NCP, whereas the N-terminus of H2A.B may somewhat compensate for the aforementioned unwrapping effect. The assembly of the H2A.B NCP is more difficult than that of the H2A NCP. H2A.B may also modulate the interactions of H1 with both the NCP and the linker DNA and could further affect the higher-order structure of the chromatin fiber. CONCLUSIONS:The results agree with the experimental results and may shed new light on the biological function of H2A.B. Multiscale modeling may be a valuable tool for investigating structure and dynamics of the nucleosome and the chromatin induced by various histone variants.

SUBMITTER: Peng J

PROVIDER: S-EPMC7362417 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Molecular mechanism of histone variant H2A.B on stability and assembly of nucleosome and chromatin structures.

Peng Junhui J Yuan Chuang C Hua Xinfan X Zhang Zhiyong Z

Epigenetics & chromatin 20200714 1

<h4>Background</h4>H2A.B, the most divergent histone variant of H2A, can significantly modulate nucleosome and chromatin structures. However, the related structural details and the underlying mechanism remain elusive to date. In this work, we built atomic models of the H2A.B-containing nucleosome core particle (NCP), chromatosome, and chromatin fiber. Multiscale modeling including all-atom molecular dynamics and coarse-grained simulations were then carried out for these systems.<h4>Results</h4>I ...[more]

PMID: 32664941

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Project description:Herpes simplex virus 1 (HSV-1) transcription is restricted in latently infected neurons and the genomes are in mostly silenced chromatin, whereas all viral genes are transcribed in lytically infected cells, in which the genomes are dynamically chromatinized. Epigenetic regulation modulates HSV-1 transcription during lytic, latent, and reactivating infections but the precise mechanisms are not fully defined. Nucleosomes are dynamic: they slide, breathe, assemble, and disassemble. We and others have proposed that the most dynamic HSV-1 chromatin is transcriptionally competent, whereas the least dynamic is silenced. However, the mechanisms yielding the unusually dynamic viral chromatin remain unknown. Histone variants affect nucleosome dynamics. The dynamics of H2A, H2A.X, and macroH2A were enhanced in infected cells, whereas those of H2A.B were uniquely decreased. We constructed stably transduced cells expressing tagged histone H2A, H2A.B, macroH2A, or H2B, which assembles the H2A/H2B nucleosome dimers with all H2A variants. All H2A variants, as well as ectopic and endogenous H2B were assembled into HSV-1 chromatin evenly throughout the genome but canonical H2A was relatively depleted whereas H2A.B was enriched, particularly in the most dynamic viral chromatin. When viral transcription and DNA replication were restricted, H2A.B became as depleted from the viral chromatin through the entire genome as H2A. We propose that lytic HSV-1 nucleosomes are enriched in the dynamic variant H2A.B/H2B dimers to promote HSV-1 chromatin dynamics and transcriptional competency and conclude that the dynamics of HSV-1 chromatin are determined in part by the H2A variants.ImportanceHerpes simplex virus 1 (HSV-1) transcription is epigenetically regulated during latent and lytic infections, and epigenetic inhibitors have been proposed as potential antiviral drugs to modulate latency and reactivation. However, the detailed epigenetic mechanisms of regulation of HSV-1 transcription have not been fully characterized and may differ from those regulating cellular transcription. Whereas lytic HSV-1 chromatin is unusually dynamic, latent silenced HSV-1 chromatin is not. The mechanisms resulting in the unique dynamics of the lytic chromatin remain unknown. Here we identify the enrichment of the highly dynamic histone 2A variant H2A in the most dynamic viral chromatin, which provides a mechanistic understanding of its unique dynamics. Future work to identify the mechanisms of enrichment in H2A.B on the viral chromatin may identify novel druggable epigenetic regulators that modulate HSV-1 latency and reactivation.

Dataset Information

Molecular mechanism of histone variant H2A.B on stability and assembly of nucleosome and chromatin structures.

Publications

Molecular mechanism of histone variant H2A.B on stability and assembly of nucleosome and chromatin structures.

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