Genome folding and nuclear speckles converge to orchestrate fibroblast activation

Fibroblasts adopt diverse cell states in response to inductive cues to maintain tissue homeostasis. We leveraged this cell-state plasticity to define how genome organization contributes to changes in cellular identity. We show that TGF-β reconfigures topologically associating domains and chromatin loops at genes upregulated during fibroblast activation into myofibroblasts. Cohesin is required for gene induction during fibroblast activation, and enhanced cohesin stability is sufficient to bypass TGF-β signaling and drive a myofibroblast-like state. Emerging evidence suggests chromatin spatial positioning relative to nuclear speckles can regulate gene expression. Therefore, we examined the role of the critical nuclear speckle component SON and showed that it is required for myofibroblast gene expression. Notably, enhancing genome folding partially rescued gene expression in fibroblasts with SON-depleted nuclear speckles. Together, these findings advance our understanding of fibrosis and support a model in which distinct facets of genome organization converge to orchestrate cell-state transitions.