Temporal Stretch-Induced Nuclear Mechanosensing Coordinates Early Chromatin Accessibility and Genome Protection

Area of Science:

• Cell Biology
• Biophysics
• Epigenetics

Background:

• Cells mechanically sense stimuli, influencing nuclear organization and gene expression.
• The precise spatiotemporal dynamics of nuclear mechanosensing are not fully understood.

Purpose of the Study:

• To investigate nuclear responses to temporal cyclic stretching in human dermal fibroblasts.
• To elucidate the cascade of mechanosensitive events linking cytoskeletal remodeling, chromatin accessibility, and gene expression.

Main Methods:

• Temporal cyclic stretching of human dermal fibroblasts.
• Analysis of chromatin decondensation, nuclear softening, H3K9me3 levels, and perinuclear actin assembly.
• Investigated Ca2+ release, emerin translocation, and genome-wide chromatin accessibility.
• Utilized in vivo skin tissue models and spatial transcriptomics.

Main Results:

• Cyclic stretch induced rapid chromatin decondensation and nuclear softening, with reduced H3K9me3.
• Perinuclear actin assembly, driven by Ca2+ release, correlated with decreased H3K9me3 via emerin translocation.
• Genome-wide profiling showed increased accessibility of mechanotransduction and DNA damage repair loci.
• Failure to coordinate these events led to DNA damage, highlighting a protective biophysical mechanism.

Conclusions:

• Temporally regulated mechanical forces trigger nuclear mechanosensing responses.
• Perinuclear mechanosensitive molecules link to epigenetic remodeling and cell fate.
• Actin-dependent pathways mediate mechanosensitive chromatin reorganization in dermal fibroblasts.