@article{58e0dbea661c47cfb40e8ee4c0641596,
title = "Physicochemical mechanotransduction alters nuclear shape and mechanics via heterochromatin formation",
abstract = "The nucleus houses, organizes, and protects chromatin to ensure genome integrity and proper gene expression, but how the nucleus adapts mechanically to changes in the extracellular environment is poorly understood. Recent studies have revealed that extracellular physical stresses induce chromatin compaction via mechanotransductive processes. We report that increased extracellular multivalent cations lead to increased heterochromatin levels through activation of mechanosensitive ion channels (MSCs), without large-scale cell stretching. In cells with perturbed chromatin or lamins, this increase in heterochromatin suppresses nuclear blebbing associated with nuclear rupture and DNA damage. Through micromanipulation force measurements, we show that this increase in heterochromatin increases chromatin-based nuclear rigidity, which protects nuclear morphology and function. In addition, transduction of elevated extracellular cations rescues nuclear morphology in model and patient cells of human diseases, including progeria and the breast cancer model cell line MDA-MB-231. We conclude that nuclear mechanics, morphology, and function can be modulated by cell sensing of the extracellular environment through MSCs and consequent changes to histone modification state and chromatin-based nuclear rigidity.",
author = "Stephens, {Andrew D.} and Liu, {Patrick Z.} and Viswajit Kandula and Haimei Chen and Almassalha, {Luay M.} and Cameron Herman and Vadim Backman and Thomas O'Halloran and Adam, {Stephen A.} and Goldman, {Robert D.} and Banigan, {Edward J.} and Marko, {John F.}",
note = "Funding Information: H.C. and T.V.O. are supported by Physical Science–Oncology Center, National Cancer Institute, Grant U54CA193419. L.M.A. and V.B. are supported by NIH grants R01CA200064 and R01CA155284, NSF grant CBET-1240416, and the Lungevity Foundation. This work was funded by the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust through a Postdoctoral Fellowship to A.D.S. Funding Information: We thank Yixian Zheng for providing us with MEF LB1-/-cells (Shimi et al., 2015). We thank Aykut Erbas¸, Sumitabha Brahmachari, and Ronald Biggs for helpful discussions. We thank Reza Vafabakhsh and Michael Schamber for advising us regarding the transient calcium influx experiments. We thank QBIC at Northwestern University for ICP-MS analysis. We thank the Northwestern Biological Imaging Facility and Director Jessica Hornick for use of the Delta Vision microscope for time lapse imaging. A.D.S. is supported by Pathway to Independence Award NIHGMS K99GM123195. A.D.S., P.Z.L, E.J.B., and J.F.M. are supported by National Science Foundation (NSF) Grants DMR-1206868 and MCB-1022117 and by National Institutes of Health (NIH) grants GM-105847, CA-193419, and, via subcontract, DK-107980. S.A.A. and R.D.G. are supported by NIH GM-106023, CA 193419, and Progeria Research Foundation PRF 2013-51. Funding Information: We thank Yixian Zheng for providing us with MEF LB1-/- cells (Shimi et al., 2015). We thank Aykut Erba?, Sumitabha Brahmachari, and Ronald Biggs for helpful discussions. We thank Reza Vafabakhsh and Michael Schamber for advising us regarding the transient calcium influx experiments. We thank QBIC at Northwestern University for ICP-MS analysis. We thank the Northwestern Biological Imaging Facility and Director Jessica Hornick for use of the Delta Vision microscope for time lapse imaging. A.D.S. is supported by Pathway to Independence Award NIHGMS K99GM123195. A.D.S., P.Z.L, E.J.B., and J.F.M. are supported by National Science Foundation (NSF) Grants DMR-1206868 and MCB-1022117 and by National Institutes of Health (NIH) grants GM-105847, CA-193419, and, via subcontract, DK-107980. S.A.A. and R.D.G. are supported by NIH GM-106023, CA 193419, and Progeria Research Foundation PRF 2013-51. H.C. and T.V.O. are supported by Physical Science?Oncology Center, National Cancer Institute, Grant U54CA193419. L.M.A. and V.B. are supported by NIH grants R01CA200064 and R01CA155284, NSF grant CBET-1240416, and the Lungevity Foundation. This work was funded by the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust through a Postdoctoral Fellowship to A.D.S. Publisher Copyright: {\textcopyright} 2019 Stephens, Liu, et al.",
year = "2019",
month = aug,
day = "1",
doi = "10.1091/mbc.E19-05-0286",
language = "English (US)",
volume = "30",
pages = "2320--2330",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "17",
}