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Histone variant H2A.Z modulates nucleosome dynamics to promote DNA accessibility.

ABSTRACT: Nucleosomes, containing histone variants H2A.Z, are important for gene transcription initiation and termination, chromosome segregation and DNA double-strand break repair, among other functions. However, the underlying mechanisms of how H2A.Z influences nucleosome stability, dynamics and DNA accessibility are not well understood, as experimental and computational evidence remains inconclusive. Our modeling efforts of human nucleosome stability and dynamics, along with comparisons with experimental data show that the incorporation of H2A.Z results in a substantial decrease of the energy barrier for DNA unwrapping. This leads to the spontaneous DNA unwrapping of about forty base pairs from both ends, nucleosome gapping and increased histone plasticity, which otherwise is not observed for canonical nucleosomes. We demonstrate that both N- and C-terminal tails of H2A.Z play major roles in these events, whereas the H3.3 variant exerts a negligible impact in modulating the DNA end unwrapping. In summary, our results indicate that H2A.Z deposition makes nucleosomes more mobile and DNA more accessible to transcriptional machinery and other chromatin components.

SUBMITTER: Li S

PROVIDER: S-EPMC9918499 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Histone variant H2A.Z modulates nucleosome dynamics to promote DNA accessibility.

Li Shuxiang S Wei Tiejun T Panchenko Anna R AR

Nature communications 20230211 1

Nucleosomes, containing histone variants H2A.Z, are important for gene transcription initiation and termination, chromosome segregation and DNA double-strand break repair, among other functions. However, the underlying mechanisms of how H2A.Z influences nucleosome stability, dynamics and DNA accessibility are not well understood, as experimental and computational evidence remains inconclusive. Our modeling efforts of human nucleosome stability and dynamics, along with comparisons with experiment ...[more]

PMID: 36765119

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Project description:The incorporation of histone variant H2A.Z into nucleosomes creates specialized chromatin domains that regulate DNA-templated processes, such as gene transcription. In Saccharomyces cerevisiae, the diverging H2A.Z C terminus is thought to provide the H2A.Z exclusive functions. To elucidate the roles of this H2A.Z C terminus genome-wide, we used derivatives in which the C terminus was replaced with the corresponding region of H2A (ZA protein), or the H2A region plus a transcriptional activating peptide (ZA-rII'), with the intent of regenerating the H2A.Z-dependent regulation globally. The distribution of these H2A.Z derivatives indicates that the H2A.Z C-terminal region is crucial for both maintaining the occupation level of H2A.Z and the proper positioning of targeted nucleosomes. Interestingly, the specific contribution on incorporation efficiency versus nucleosome positioning varies enormously depending on the locus analyzed. Specifically, the role of H2A.Z in global transcription regulation relies on its C-terminal region. Remarkably, however, this mostly involves genes without a H2A.Z nucleosome in the promoter. Lastly, we demonstrate that the main chaperone complex which deposits H2A.Z to gene regulatory region (SWR1-C) is necessary to localize all H2A.Z derivatives at their specific loci, indicating that the differential association of these derivatives is not due to impaired interaction with SWR1-C. IMPORTANCE We provide evidence that the Saccharomyces cerevisiae C-terminal region of histone variant H2A.Z can mediate its special function in performing gene regulation by interacting with effector proteins and chaperones. These functional interactions allow H2A.Z not only to incorporate to very specific gene regulatory regions, but also to facilitate the gene expression process. To achieve this, we used a chimeric protein which lacks the native H2A.Z C-terminal region but contains an acidic activating region, a module that is known to interact with components of chromatin-remodeling entities and/or transcription modulators. We reasoned that because this activating region can fulfill the role of the H2A.Z C-terminal region, at least in part, the role of the latter would be to interact with these activating region targets.

Dataset Information

Histone variant H2A.Z modulates nucleosome dynamics to promote DNA accessibility.

Publications

Histone variant H2A.Z modulates nucleosome dynamics to promote DNA accessibility.

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