Periodontal disease is characterized by progressive degradation of the gingival extracellular matrix and loss of the physical confinement it imposes on resident stromal cells. In human periodontal tissue, ECM collagen integrity is inversely correlated with facultative nuclear histone acetylation in stromal cells. We hypothesized that matrix stiffness directly coordinates an epigenomic shift in stromal cells. We use a three-dimensional mechanically tunable hydrogel system to independently tune the storage moduli across the mechanical range of healthy and periodontitis-affected gingival tissue. Matrix stiffness drives a genome-wide response in donor-derived human gingival fibroblasts. Matrix-induced confinement leads to an isotropic nuclear geometry and a folded nuclear envelope architecture compared with more permissive, soft matrices. H3K27Ac is suppressed through a stiffness and actomyosin contractility-dependent mechanism. DNMT inhibition in stiff matrices restores the high-acetylation chromatin state with persistent nuclear envelope folding. At the genomic level, stiff matrix confinement drives global CpG methylation gain concentrated at pericentromeric satellite repeats and repeat-dense regions, while collagen synthesis gene promoters and CTCF binding sites are selectively hypomethylated. Non-canonical NF-kappaB inflammatory signaling is attenuated through promoter methylation of MAP3K14, and pharmacological NIK inhibition reduces TLR2-stimulated IL-6 secretion in soft-matrix fibroblasts to levels comparable to the stiff condition. These findings identify the gingival ECM as an active epigenomic regulator of stromal inflammatory competence and provide a mechanistic rationale for targeting matrix mechanics to restore stromal homeostasis in periodontitis.
China has approved the world’s first invasive brain-computer chip—here’s what’s next
One day last October, sitting in the courtyard of his house in China’s Henan province, Dong Hui decided to see if he could hold a