Transient nuclear deformation primes epigenetic state and promotes cell reprogramming.

Area of Science:

• Biophysics
• Cell Biology
• Epigenetics

Background:

• Cell reprogramming is crucial for regenerative medicine and disease modeling.
• Mechanical forces, alongside biochemical cues, influence cell epigenetic states and functions.
• The precise mechanisms by which mechanical forces modulate epigenetics remain incompletely understood.

Purpose of the Study:

• To investigate the impact of rapid cell nucleus deformation on epigenetic modifications.
• To explore the potential of mechanical forces as a method for cell engineering and reprogramming.

Main Methods:

• Utilizing microfluidic channels to induce millisecond-scale deformation of the cell nucleus.
• Analyzing changes in nuclear lamina structure, chromatin organization, and epigenetic marks (histone and DNA methylation).
• Assessing the efficiency of cell reprogramming (fibroblasts to neurons, macrophages to neurons, fibroblasts to iPSCs) following mechanical stimulation.

Main Results:

• Millisecond nuclear deformation causes nuclear lamina wrinkling and transient disassembly.
• Mechanical stress leads to detachment of lamina-associated chromatin domains.
• A decrease in histone H3 lysine 9 trimethylation and DNA methylation was observed.
• This mechanopriming significantly boosted fibroblast-to-neuron conversion and was partially mimicked by inhibiting these methylation marks.
• Macrophage-to-neuron and fibroblast-to-iPSC reprogramming were also enhanced by this approach.

Conclusions:

• Rapid mechanical deformation of the nucleus is a potent modulator of the cell's epigenetic state.
• Mechanically induced epigenetic changes can significantly enhance cell reprogramming efficiency.
• This mechanopriming represents a novel, mechanically driven strategy for cell engineering and therapeutic applications.