Epigenetic modulation changed the secondary metabolite profile in the endophyte Nigrospora sphaerica SS67

It has been recognized that under standard laboratory conditions most microbial biosynthetic gene clusters are either silent or expressed at very low levels. Those cryptic pathways may be triggered by molecular, chemical or environmental signals The culture manipulation of fungi in the presence of DNA methyltransferase and/or HDAC inhibitors led to the enhanced expression of biosynthetic pathways and further production of new secondary metabolites. In this work we selected histone deacetylase inhibitors: sodium butyrate (a), suberohydroxamic acid (b) and valproic acid (c), and DNA methyltransferase inhibitors: 5-azacytidine (d), hydralazine (e), procainamide (f) and procaine (g) to carry out modulation epigenetic studies with endophytic fungus N. sphaerica SS67, an aphidicolin producer under usual lab conditions. The liquid cultures of the N. sphaerica SS67 were supplemented with 50µM of each epigenetic modulator and cultured for 8 days. The MeOH extracts were analyzed by HPLC-UV-DAD and LC-HRESIMS. The chromatography profiles showed different responses to the small-molecule epigenetic modifiers (a-c) and (e) which induced the production of additional compounds. The epigenetic modulation using modifiers (a), (e) and (g) showed total inhibitory effect on the biosynthesis of aphidicolin. Our results showed that this approach may trigger cryptic biosynthetic pathways for the production of silent secondary metabolites. The chemical analysis of the elicited cultures will be presented.