Chromatin accessibility regulates age-dependent nuclear mechanotransduction

Area of Science:

• Cell Biology
• Epigenetics
• Aging Research

Background:

• Cellular responses to environmental cues are vital for function.
• The impact of cellular aging on signal integration via chromatin organization is not well understood.
• Investigating age-related changes in chromatin is crucial for understanding cellular dysfunction.

Purpose of the Study:

• To investigate how age-related changes in 3D chromatin organization affect human dermal fibroblast responses to mechanical tension and TGF-β.
• To identify the molecular mechanisms underlying altered cellular responsiveness in aged cells.
• To explore potential therapeutic targets for age-related cellular decline.

Main Methods:

• Comparative analysis of young and aged human dermal fibroblasts.
• Assessment of gene expression in response to combined mechanical and TGF-β stimuli.
• Chromatin accessibility profiling.
• Identification and validation of key transcription factors involved in regulating cellular responses.

Main Results:

• Young fibroblasts showed synergistic gene expression enhancement to combined stimuli, while aged cells exhibited blunted or divergent responses.
• Significant age-related differences in chromatin accessibility correlated with altered cellular responses.
• The AP-1 complex and specific transcription factors were identified as critical regulators of these age-dependent mechanochemical responses.
• Disruption of AP-1 activity inhibited fibroblast activation by preventing JUNB recruitment.

Conclusions:

• 3D chromatin organization acts as a key integrator of mechanochemical signals.
• Age-related alterations in chromatin organization modify cellular responsiveness, leading to impaired signal integration.
• The AP-1 complex and its network represent potential therapeutic targets to counteract age-related cellular decline and restore cellular function.