m4C DNA methylation regulates biosynthesis of daptomycin in Streptomyces roseosporus L30

Abstract

Despite numerous studies on transcriptional level regulation by single genes in drug producing <i>Actinomyces</i>, the global regulation based on epigenetic modification is not well explored. N4-methylcytosine (m4C), an abundant epigenetic marker in <i>Actinomycetes</i>' genome, but its regulatory mechanism remains unclear. In this study, we identify a m4C methyltransferase (SroLm3) in <i>Streptomyces roseosporus</i> L30 and multi-omics studies were performed and revealed SroLm3 as a global regulator of secondary metabolism. Notably, three BGCs in Δ<i>sroLm3</i> strain exhibited decreased expression compared to wild type. In-frame deletion of <i>sroLm3</i> in <i>S.roseosporus</i> L30 further revealed its role in enhancing daptomycin production. In summary, we characterized a m4C methyltransferase, revealed the function of m4C in secondary metabolism regulation and biosynthesis of red pigment, and mapped a series of novel regulators for daptomycin biosynthesis dominated by m4C methylation. Our research further indicated that m4C DNA methylation may contribute to a metabolic switch from primary to secondary metabolism in <i>Actinomyces.</i>