A gene-editing and selection system for connecting epigenetic controllers to inactive natural product genes in Aspergillus nidulans

A platform was developed to identify five pairs of epigenetic regulators and silent gene clusters in Aspergillus nidulans.

• Chemical inhibition of epigenetic regulators is effective for activating silent biosynthetic gene clusters but often lacks specificity.
• A cytosine base editing and auxotrophic selection platform was created to systematically identify epigenetic regulators of silent gene clusters.
• An sgRNA library targeting 24 core epigenetic regulators was used alongside a cytosine base editor in 21 pyrG-based PKS reporter strains.
• The screen revealed known and previously uncharacterized interactions, including KdmB repressing the AN7084 gene cluster and Kmt5 silencing the cichorine core pks gene.
• These findings advance the ability to match silent biosynthetic gene clusters with their epigenetic regulators.

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