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.