In summary, we identified TRIM28 as a critical positive regulator of Th17 development, in which TRIM28 serves as an epigenetic activator downstream of STAT3 in response to cytokine signaling, and directs Th17 differentiation by regulating chromosomal activation and 3D-looping of key effector cytokine genes, and highlights epigenetic intervention as possible therapeutic approaches in treatment of Th17-related autoimmune diseases. Here, STAT3 is linked to autoimmune disease.