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, 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 mechanosensitive ion channels and consequent changes to histone modification state and chromatin-based nuclear rigidity.

Chromatin’s physical properties shape the nucleus and its functions

“…It is significant that each of these downstream chromatin perturbations -loss of connections to the periphery, decondensation, and decreased heterochromatin content -can independently induce abnormal nuclear morphology (as discussed below). Moreover, in many of these lamin-perturbed cases, normal nuclear morphologies can be rescued by restoring heterochromatin to normal levels [30,81]. This suggests that heterochromatin mechanics may dominate the regulation of nuclear shape, and that lamin defects may induce blebs indirectly through their downstream effects on chromatin and its anchoring to the nuclear periphery.…”

“…Increases in heterochromatin, in contrast, can rescue nuclear shape and rigidity. Rescue by heterochromatin has been demonstrated for both chromatin and lamin perturbations, including in cells with excess histone acetylation, lamin B1 depletion, or mutant lamin A progerin overexpression, as well as in Hutchinson-Gilford progeria syndrome patient cells [30,81]. Similarly, chromatin condensation coincides with bleb healing and reabsorption into the nuclear body [29].…”

“…External mechanical stimuli trigger mechanotransduction through mechanosensitive ion channels in the plasma membrane [98][99][100], leading to chromatin condensation and heterochromatin formation [81,94,101,102]. Mechanotransduction via mechanosensitive ion channels can increase heterochromatin levels and chromatin-based nuclear rigidity, while concurrently rescuing nuclear shape in lamin-perturbed, chromatin-pertubed, and disease model cells (e.g., progeria and breast cancer) [81]. This provides a native chromatin regulation pathway for the cell to sense and respond to the extracellular environment in order to protect nuclear shape and organization.…”

“…Similarly, chromatin condensation and compaction can be regulated through extracellular osmotic changes [103,104], compression [105], substrate micropatterning [97,106], cell substrate stretching [94,101,102,107], changes in charge composition [81], and cell migration [36,108,109]. Notably, heterochromatin levels increase during cell migration, and migration through pores can be blocked by the concurrent increase in nuclear rigidity [110].…”

“…decreased chromatin-lamina attachments and decreased heterochromatin [7,[76][77][78][79]; softer chromatin by 50% [76] increased heterochromatin [30,81] Lamin B depletion no change or stiffer (lamin A amount dependent)…”