SUN2 mediates epigenetic remodeling to drive mechanotransduction during skin fibrosis

Abstract Fibrosis involves sustained changes in fibroblast gene expression, leading to excessive extracellular matrix (ECM) deposition and progressive tissue stiffening. Although matrix stiffness is a potent regulator of cell fate and transcription, it is not clear how nuclear mechanosensing contributes to fibrosis. Here, we define a central role for SUN2, a component of linker of nucleoskeleton and cytoskeleton (LINC) complexes, as a mediator of stiffness-dependent nuclear and chromatin responses during skin fibrosis. SUN2 transcripts are upregulated in dermal fibroblasts of patients with systemic sclerosis and Sun2 protein is elevated in fibrotic mouse skin. Nuclear size, A-type lamins and Sun2 are elevated in dermal fibroblasts plated on stiff substrates. Loss of Sun2 protects against bleomycin-induced skin fibrosis in vivo and abolishes stiffness-induced changes in nuclear size and fibrotic gene expression in vitro. Mechanistically, we identify three Sun2 -dependent mechanosensitive chromatin states and show that mechanical induction of the histone methyltransferase Ezh2 requires Sun2 . These findings define SUN2 as a nuclear mechanosensor that couples matrix stiffness to chromatin regulation and transcriptional programs that drive fibrosis, identifying it as a potential therapeutic target pathway in fibrotic disease.