Response Regulator Heterodimer Formation Controls a Key Stage in Streptomyces Development

The orphan, atypical response regulators BldM and Whil each play critical roles in Streptomyces differentiation. BldM is required for the formation of aerial hyphae, and Whil is required for the differentiation of these reproductive structures intomature spores. To gain insight into BldMfunction, we defined the genome-wide BldM regulon using ChlP-Seq and transcriptional profiling. BldM target genes clustered into two groups based on their whi gene dependency. Expression of Group I genes depended on bldM but was independent of all the whi genes, and biochemical experiments showed that Group I promoters were controlled by a BldM homodimer. In contrast, Group II genes were expressed later than Group I genes and their expression depended not only on bldM but also on whil and whiG (encoding the sigma factor that activates whil). Additional ChlP-Seq analysis showed that BldMGroup II genes were also direct targets of Whil and that in vivo binding of Whil to these promoters depended on BldM and vice versa. We go on to demonstrate that BldM and Whil form a functional heterodimer that controls Group II promoters, serving to integrate signals from two distinct developmental pathways. The BldM-Whil system thus exemplifies the potential of response regulator heterodimer formation as a mechanism to expand the signaling capabilities of bacterial cells.