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During biliary disease, cholangiocytes become activated by various pathological stimuli, including transforming growth factor β (TGF‐β). The result is an epigenetically regulated transcriptional program leading to a pro‐fibrogenic microenvironment, activation of hepatic stellate cells (HSCs), and progression of biliary fibrosis. This study evaluated how TGF‐β signaling intersects with epigenetic machinery in cholangiocytes to support fibrogenic gene transcription. We performed RNA sequencing in cholangiocytes with or without TGF‐β. Ingenuity pathway analysis identified “HSC Activation” as the highly up‐regulated pathway, including overexpression of fibronectin 1 (FN), connective tissue growth factor, and other genes. Bioinformatics identified enhancer of zeste homologue 2 (EZH2) as an epigenetic regulator of the cholangiocyte TGF‐β response. EZH2 overexpression suppressed TGF‐β‐induced FN protein in …