Chromatin-mediated upregulation of Monascus pigments in Talaromyces purpurogenus OUCMDZ-019 via disruption of Ash2.

Monascus pigments (MPs) are important azaphilone-type polyketide pigments, yet yield control, stability, and safety pose challenges. Using an epigenetic derepression strategy, we constructed an Ash2 deletion mutant in the acidophilic fungus Talaromyces purpurogenus OUCMDZ-019, with Ash2 being a COMPASS subunit involved in H3K4 methylation. Transcriptomic analysis revealed broad transcriptional changes, including marked upregulation of an MPs-related BGC, accompanied by pronounced metabolome remodeling. Integrating genome mining, transcriptomics, and GNPS molecular networking enabled targeted isolation of twelve MP derivatives, including four new azaphilones (talarpurpurones A-D), whose absolute configurations were confirmed by spectroscopy. pH-dependent transformation experiments clarified the behavior of azaphilic addition, providing insight into pigment interconversion and composition drift during fermentation. Talarpurpurone A exhibited high color value and stable red coloration from pH 3 to 11, outperforming commercial preparations. These pigments displayed selected moderate activity against Gram-positive bacteria and lipid-lowering activity. Notably, bioinformatic and fermentation analysis supported the absence of citrinin biosynthesis in OUCMDZ-019. Overall, these results suggest that Ash2 deletion is associated with azaphilone pigment diversification in Talaromyces under the tested conditions and provide a citrinin-free fungal strain for MPs production.