Transient nuclear deformation primes epigenetic state and promotes cell reprogramming

Cell reprogramming has wide applications in tissue regeneration, disease modelling and personalized medicine. In addition to biochemical cues, mechanical forces also contribute to the modulation of the epigenetic state and a variety of cell functions through distinct mechanisms that are not fully understood. Here we show that millisecond deformation of the cell nucleus caused by confinement into microfluidic channels results in wrinkling and transient disassembly of the nuclear lamina, local detachment of lamina-associated domains in chromatin and a decrease of histone methylation (histone H3 lysine 9 trimethylation) and DNA methylation. These global changes in chromatin at the early stage of cell reprogramming boost the conversion of fibroblasts into neurons and can be partially reproduced by inhibition of histone H3 lysine 9 and DNA methylation. This mechanopriming approach also triggers macrophage reprogramming into neurons and fibroblast conversion into induced pluripotent stem cells, being thus a promising mechanically based epigenetic state modulation method for cell engineering. Mechanical confinement of fibroblasts into micrometre-sized channels deforms the cell nucleus, leading to temporary nuclear lamina destablization and disassembly, loss of lamina-associated domains in chromatin and a decrease in histone and DNA methylation. These mechanically induced alterations in chromatin boost the conversion of fibroblasts into neurons and pluripotent stem cells and thus can be explored for cell engineering applications.

Automated summary

Deformation of the cell nucleus boosts cell reprogramming and offers potential applications in cell engineering.