Genome folding and nuclear speckles converge to orchestrate fibroblast activation

Fibroblasts maintain tissue homeostasis yet readily adopt diverse cell states in response to stimuli, making them a powerful model system in which to study this balance. Three-dimensional genome organization is a key mechanism by which cells coordinate gene expression programs, but its role in shaping cellular identity remains unclear.

Here, we show that TGF-β stimulation rewires topologically associating domain organization and chromatin looping at upregulated genes prior to the acquisition of a myofibroblast identity. Proper cohesin function was required for gene induction and myofibroblast differentiation, while enhanced cohesin stability was sufficient to bypass TGF-β signaling and drive a myofibroblast-like state. Given the role of cohesin in gene induction and growing evidence indicating chromatin positioning relative to nuclear landmarks can induce gene expression, we examined the role of the nuclear speckle.