Deciphering the regulon of the Streptomyces coelicolor AbrC3, a positive response regulator of antibiotic production.

The atypical two-component system (TCS) AbrC1/2/3 (encoded respectively by SCO4598/4597/4596), comprising two histidine kinases (HKs) and a response regulator (RR), is crucial for antibiotic production in Streptomyces coelicolor and for morphological differentiation under certain nutritional conditions. In this study we demonstrate that deletion of the RR-encoding gene abrC3, SCO4596, results in a dramatic decrease in ACT and RED production and delays morphological development. In contrast, the over-expression of abrC3 in the parent strain leads to a 33% increase in ACT production in liquid medium. Transcriptomic and ChIP-chip analyses of ΔabrC3 and the parent strain revealed that AbrC3 directly controls ACT production by binding to the actII-ORF4 promoter region; this was independently verified by in vitro DNA-binding assays. This binding is dependent on the sequence (5' -GAASGSGRMS-3' ). In contrast, the regulation of RED production is not due to direct binding of AbrC3, either to the redZ or to the redD promoters regions. This study also revealed other members of the AbrC3 regulon: AbrC3 is a positive autoregulator, which also binds to the promoter regions of SCO0736, bdtA (SCO3328), absR1 (SCO6992), and SCO6809. The direct targets share the ten-base consensus binding sequence and may be responsible for some of the phenotypes of the ΔabrC3 mutant. The identification of the AbrC3 regulon as part of the complex regulatory network governing antibiotic production widens our knowledge regarding TCS involvement in control of antibiotic synthesis and may contribute to the rational design of new hyper-producer host strains through genetic manipulation of such systems