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Mol Biol Cell. 2018 Jan 15;29(2):220-233. doi: 10.1091/mbc.E17-06-0410. Epub 2017 Nov 15.

Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins.

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Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208
Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208.
Department of Physics and Astronomy, Northwestern University, Evanston, IL 60208.
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208.
Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.


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. Conversely, 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.

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