# Chromatin accessibility regulates age-dependent nuclear mechanotransduction

## TL;DR

Aging changes how cells respond to mechanical and biochemical signals by altering chromatin structure, with AP-1 playing a key role in this process.

## Contribution

The study reveals that chromatin accessibility regulates mechanochemical signaling during aging, with AP-1 as a master regulator.

## Key findings

- Aged fibroblasts lose synergistic responses to mechanical and TGF-β stimulation due to chromatin accessibility changes.
- AP-1 and related transcription factors are pivotal in remodeling chromatin and orchestrating mechanochemical responses during aging.
- Disrupting AP-1 activity inhibits fibroblast activation by preventing JUNB recruitment to the transcription machinery.

## Abstract

Although cells continuously integrate diverse environmental cues, the mechanisms by which aging reprograms mechanical and biochemical signaling remain poorly understood. We demonstrate that aged fibroblasts lose the capacity to mount synergistic responses to simultaneous mechanical and TGF-β stimulation, driven by age-dependent alterations in chromatin accessibility. These findings establish a paradigm in which 3D genome architecture functions as a critical regulator of mechanochemical information, and its age-related dysregulation reprograms cellular responsiveness. We further identify the AP-1 network as a master regulator of this process.

The integration of environmental cues into cellular programs is crucial for cell function. Yet, how this integration is modulated due to cellular aging remains unclear. We propose that the 3D chromatin organization filters these signals and investigated how age-related chromatin changes in human dermal fibroblasts affect responses to mechanical tension and TGF-β. Young fibroblasts exhibited synergistic gene expression enhancement in response to combined stimuli, a response that was markedly blunted or divergent in aged cells. These distinct outcomes correlated with significant age-related differences in chromatin accessibility. We identified the AP-1 complex and other transcription factors with age-specific activity as pivotal in remodeling chromatin and orchestrating these divergent mechanochemical responses during cellular aging. We validated that disrupting AP-1 activity inhibits fibroblast activation by preventing JUNB recruitment to the transcription machinery. Our findings establish chromatin as a key integrator of mechanochemical signals and characterize the age-related alterations to this integration that modify the cellular responsiveness of aged cells, highlighting AP-1 and its network as potential therapeutic targets against age-related decline.