Hypothesis

Integrin‑FAK‑ROCK signaling sets nuclear tension that gates the recruitment of the H3K9me3 demethylase KDM4D to lamina‑associated chromatin, determining whether excitatory neurons undergo age‑dependent heterochromatin erosion and LINE1 reactivation while inhibitory neurons retain a youthful state.

Mechanistic model

In young excitatory neurons, high integrin β1–FAK activity promotes actomyosin contractility, stretching the nucleus and keeping lamina‑associated domains (LADs) compact. This physical strain excludes KDM4D from H3K9me3‑rich heterochromatin, preserving silencing of LINE1 elements. With age, chronic low‑grade inflammation reduces integrin ligand availability, diminishing FAK‑ROCK signaling and nuclear tension. The relaxed nucleus allows LADs to drift inward, exposing H3K9me3 marks to KDM4D, which demethylates them, leading to chromatin decompaction, increased ATAC‑seq signal at repetitive elements, and transcriptional activation of LINE1. The resulting cytosolic nucleic acids trigger cGAS‑STING signaling, reinforcing the low‑tension state through autocrine IFN‑mediated suppression of integrin expression—a positive feedback loop.

Inhibitory neurons maintain a distinct integrin repertoire (elevated integrin α5β1) that sustains FAK signaling despite the inflammatory milieu, preserving nuclear tension and blocking KDM4D access, thereby protecting their heterochromatin.

Neural stem cells integrate this mechanosensitive switch with their activation state. Quiescent NSCs exhibit low integrin‑FAK tone, resulting in reduced nuclear tension that closes adhesion/migration gene enhancers (low ATAC‑seq signal). Upon activation, integrin signaling spikes, nuclear tension rises, and the same enhancers become accessible (high ATAC‑seq), promoting migration. ROCK inhibition lowers actomyosin contractility, decreasing tension and paradoxically restoring a youthful accessibility pattern by reducing KDM4D‑driven heterochromatin loss at LADs, thereby uncoupling the migration defect from cytoskeletal dynamics alone.

Testable predictions

• Genetic loss of integrin β1 in excitatory neurons (using Camk2a‑Cre;Itgb1^fl^fl mice) will prematurely recapitulate the aged chromatin landscape: increased ATAC‑seq signal at heterochromatin repeats, elevated LINE1 RNA, and reduced H3K9me3 ChIP‑seq signal in young adults.
• Pharmacological FAK activation (e.g., Y15 agonist) delivered to aged mice will rescue nuclear tension, restore H3K9me3 levels at LADs, suppress LINE1 transcription, and normalize ATAC‑seq profiles without affecting global histone acetylation.
• Optogenetic increase of nuclear tension in aged NSCs (via CRY2‑CIBN tethered to LINC complexes) will shift the accessibility of adhesion/migration genes toward the activated state, improving migration in vitro and neurogenesis in vivo, independent of ROCK inhibition.
• Induced nuclear tension relaxation in inhibitory neurons (through shRNA‑mediated knock‑down of Itgα5) will mimic the excitatory neuron aging phenotype, producing heterochromatin loss and LINE1 activation.

These experiments directly test whether integrin‑FAK‑ROCK‑driven nuclear tension is the upstream regulator that coordinates cell‑type‑specific heterochromatin maintenance, LINE1 silencing, and activation‑state‑dependent chromatin remodeling in aging stem cells.