Abstract
The orphan, atypical response regulators BldM and WhiI each play critical roles in Streptomyces differentiation. BldM is required for the formation of aerial hyphae, and WhiI is required for the differentiation of these reproductive structures into mature spores. To gain insight into BldM function, we defined the genome-wide BldM regulon using ChIP-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 whiI and whiG (encoding the sigma factor that activates whiI). Additional ChIP-Seq analysis showed that BldM Group II genes were also direct targets of WhiI and that in vivo binding of WhiI to these promoters depended on BldM and vice versa. We go on to demonstrate that BldM and WhiI form a functional heterodimer that controls Group II promoters, serving to integrate signals from two distinct developmental pathways. The BldM-WhiI system thus exemplifies the potential of response regulator heterodimer formation as a mechanism to expand the signaling capabilities of bacterial cells.
Highlights
Two-component signal transduction systems are of central importance in regulating gene expression in bacteria
Our data show that BldM activates transcription of these Group II genes as a BldMWhiI heterodimer, while activating transcription of the Group I genes required for the early stages of development as a BldM homodimer
This work significantly expands our knowledge of the regulatory network that controls morphological differentiation in Streptomyces (Figure 7), an advance made possible by exploiting S. venezuelae as a new model species for the genus
Summary
Two-component signal transduction systems are of central importance in regulating gene expression in bacteria. They consist of a response regulator, which functions as a homodimer, and a cognate sensor histidine kinase (which may function as a cognate phosphatase). The sensor kinase autophosphorylates on a conserved histidine residue, and the phosphoryl group is transferred to a conserved aspartate in the response regulator. The addition of the phosphoryl group stabilizes a conformation of the response regulator that drives an output response, most often the activation of gene expression. The intrinsic modularity of these systems has allowed bacteria to evolve variations on this basic theme, including more complex multicomponent phosphorelays, and changes in the nature of the response regulator effector domain such that the output can be, for example, an enzymatic activity rather than DNA binding [1,2,3].
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