Regarding targeted disruption of epigenetic regulators, histone methyltransferase and deacetylase in a plant endophytic fungus Pestalotiopsis fici have been uncovered as an unexplored chemical repertoire. Manipulation of epigenetic regulators led to the isolation of 15 new polyketides, including pestaloficiols T-W (1-3 and 5), as well as 11 macrodiolide ficiolides A-K (6-16). Ficiolide K (16) was found to contain a very rare 1,6-anhydro-pyranose moiety. Finally, the biosynthetic origin of macrodiolide was characterized by isotope-labeling experiments.