Physicochemical mechanotransduction alters nuclear shape and mechanics via heterochromatin formation

Andrew D. Stephens, Patrick Z. Liu, Viswajit Kandula, Haimei Chen, Luay M. Almassalha, Cameron Herman, Vadim Backman, Thomas V O'Halloran, Stephen A Adam, Robert Goldman, Edward J. Banigan, John F Marko

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2320-2330
Number of pages11
JournalMolecular biology of the cell
Volume30
Issue number17
DOIs
StatePublished - Aug 1 2019

Fingerprint

Heterochromatin
Mechanics
Chromatin
Ion Channels
Cations
Histone Code
Progeria
Micromanipulation
Lamins
Blister
DNA Damage
Rupture
Genome
Breast Neoplasms
Gene Expression
Cell Line

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Stephens, Andrew D. ; Liu, Patrick Z. ; Kandula, Viswajit ; Chen, Haimei ; Almassalha, Luay M. ; Herman, Cameron ; Backman, Vadim ; O'Halloran, Thomas V ; Adam, Stephen A ; Goldman, Robert ; Banigan, Edward J. ; Marko, John F. / Physicochemical mechanotransduction alters nuclear shape and mechanics via heterochromatin formation. In: Molecular biology of the cell. 2019 ; Vol. 30, No. 17. pp. 2320-2330.
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Physicochemical mechanotransduction alters nuclear shape and mechanics via heterochromatin formation. / Stephens, Andrew D.; Liu, Patrick Z.; Kandula, Viswajit; Chen, Haimei; Almassalha, Luay M.; Herman, Cameron; Backman, Vadim; O'Halloran, Thomas V; Adam, Stephen A; Goldman, Robert; Banigan, Edward J.; Marko, John F.

In: Molecular biology of the cell, Vol. 30, No. 17, 01.08.2019, p. 2320-2330.

Research output: Contribution to journalArticle

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AU - Stephens, Andrew D.

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AU - Herman, Cameron

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AU - Marko, John F

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