Abstract
Since Robert Feulgen first stained DNA in the cell, visualizing genome chromatin has been a central issue in cell biology to uncover how chromatin is organized and behaves in the cell. To approach this issue, we have developed single-molecule imaging of nucleosomes, a basic unit of chromatin, to unveil local nucleosome behavior in living cells. In this study, we investigated behaviors of nucleosomes with various histone H4 mutants in living HeLa cells to address the role of H4 tail acetylation, including H4K16Ac and others, which are generally associated with more transcriptionally active chromatin regions. We ectopically expressed wild-type (wt) or mutated H4s (H4K16 point; H4K5,8,12,16 quadruple; and H4 tail deletion) fused with HaloTag in HeLa cells. Cells that expressed wtH4-Halo, H4K16-Halo mutants, and multiple H4-Halo mutants had euchromatin-concentrated distribution. Consistently, the genomic regions of the wtH4-Halo nucleosomes corresponded to Hi-C contact domains (or topologically associating domains, TADs) with active chromatin marks (A-compartment). Utilizing single-nucleosome imaging, we found that none of the H4 deacetylation or acetylation mimicked H4 mutants altered the overall local nucleosome motion. This finding suggests that H4 mutant nucleosomes embedded in the condensed euchromatic domains with excess endogenous H4 nucleosomes cannot cause an observable change in the local motion. Interestingly, H4 with four lysine-to-arginine mutations displayed a substantial freely diffusing fraction in the nucleoplasm, whereas H4 with a truncated N-terminal tail was incorporated in heterochromatic regions as well as euchromatin. Our study indicates the power of single-nucleosome imaging to understand individual histone/nucleosome behavior reflecting chromatin environments in living cells.
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The data have been deposited with links to BioProject accession numbers PRJDB17378 (H2B-HaloTag pull-down) and PRJDB17379 (H4-HaloTag pull-down) in the DDBJ BioProject database.
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Acknowledgements
We are grateful to Dr. K. M. Marshall for critical reading and editing of this manuscript. We thank Dr. H. Kimura for providing his antibodies, Dr. K. Hibino, Mr. M. A. Shimazoe, and Maeshima laboratory members for their helpful discussions and support. This work was supported by JSPS grants JP24H00061 (K. Maeshima), JP21H02453 (K. Maeshima), JP20H05936 (K. Maeshima), JP22H05606 (S. Ide), JP23K17398 (K. Maeshima, S. Ide), JP21H02535 (S. Ide), JP22H04925 (PAGS) (K. Maeshima), and Takeda Science Foundation (K. Maeshima). A.S. is a MEXT Scholar. S. Iida and K. Minami were SOKENDAI Special Researchers (JST SPRING JPMJSP2104) and are currently JSPS Fellows (S. Iida, JP23KJ0996; K. Minami, JP23KJ0998).
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Ministry of Education, Culture, Sports, Science and Technology, Japan Society for the Promotion of Science, JP23KJ0996, JP23KJ0998, JP22H05606, JP23K17398, JP24H00061, JP21H02453, JP20H05936, JP21H02535, JP22H04925 (PAGS), Japan Science and Technology Agency, JPMJSP2104, and Takeda Science Foundation.
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A.S. and K. Maeshima designed the project. A.S. constructed mutants of histone H4 and created the cell lines with help of S. Ide and S. Iida. A. S. and S. Iida performed single-nucleosome imaging, tracking, and analysis. A.S. performed the cell biology experiments with help of S. Iida. S.T. and K. Minami purified H4-Halo labeled nucleosomal DNA and prepared sequencing library with help of S. Ide. A.T. performed sequencing. K.H. and K.K. analyzed the sequencing data. A.S., S. Iida., and K. Maeshima wrote the manuscript with input from all the authors.
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Semeigazin, A., Iida, S., Minami, K. et al. Behaviors of nucleosomes with mutant histone H4s in euchromatic domains of living human cells. Histochem Cell Biol (2024). https://doi.org/10.1007/s00418-024-02293-x
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DOI: https://doi.org/10.1007/s00418-024-02293-x