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Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins

View ORCID ProfileAndrew D. Stephens, Patrick Z. Liu, Edward J. Banigan, Luay M. Almassalha, Vadim Backman, Stephen A. Adam, Robert D. Goldman, John F. Marko
doi: https://doi.org/10.1101/206367
Andrew D. Stephens
1Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208
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  • For correspondence: andrew.stephens@northwestern.edu
Patrick Z. Liu
1Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208
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Edward J. Banigan
2Department of Physics and Astronomy, Northwestern University, Evanston, IL 60208
3Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139
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Luay M. Almassalha
4Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208
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Vadim Backman
4Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208
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Stephen A. Adam
5Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
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Robert D. Goldman
5Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
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John F. Marko
1Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208
2Department of Physics and Astronomy, Northwestern University, Evanston, IL 60208
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Abstract

Nuclear shape and architecture influence gene localization, mechanotransduction, transcription, and cell function. Abnormal nuclear morphology and protrusions termed “blebs” are diagnostic markers for many human afflictions including heart disease, aging, progeria, and cancer. Nuclear blebs are associated with both lamin and chromatin alterations. A number of prior studies suggest that lamins dictate nuclear morphology, but the contributions of altered chromatin compaction remain unclear. We show that chromatin histone modification state dictates nuclear rigidity, and modulating it is sufficient to both induce and suppress nuclear blebs. Treatment of mammalian cells with histone deacetylase inhibitors to increase euchromatin or histone methyltransferase inhibitors to decrease heterochromatin results in a softer nucleus and nuclear blebbing, without perturbing lamins. Oppositely, treatment with histone demethylase inhibitors increases heterochromatin and chromatin nuclear rigidity, which results in reduced nuclear blebbing in lamin B1 null nuclei. Notably, increased heterochromatin also rescues nuclear morphology in a model cell line for the accelerated aging disease Hutchinson-Gilford progeria syndrome caused by mutant lamin A, as well as cells from patients with the disease. Thus, chromatin histone modification state is a major determinant of nuclear blebbing and morphology via its contribution to nuclear rigidity.

Footnotes

  • Abbreviations
    HDACi
    histone deacetylase inhibitor
    HMTi
    histone methyltransferase inhibitor
    HDMi
    histone demethylase inhibitor
    V-/-
    vimentin null
    LB1-/-
    lamin B1 null
    HGPS
    Hutchinson-Gilford progeria syndrome

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted October 29, 2017.
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Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins
Andrew D. Stephens, Patrick Z. Liu, Edward J. Banigan, Luay M. Almassalha, Vadim Backman, Stephen A. Adam, Robert D. Goldman, John F. Marko
bioRxiv 206367; doi: https://doi.org/10.1101/206367
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Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins
Andrew D. Stephens, Patrick Z. Liu, Edward J. Banigan, Luay M. Almassalha, Vadim Backman, Stephen A. Adam, Robert D. Goldman, John F. Marko
bioRxiv 206367; doi: https://doi.org/10.1101/206367

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