The Gene Regulatory Network of Mycobacterium tuberculosis, v1.0

The bacterial pathogen Mycobacterium tuberculosis (MTB) infects 30% of all humans and kills someone every 20 – 30 seconds.  In the push for new interventions, we have recently taken the first steps towards a complete reconstruction of the Mycobacterium tuberculosis (MTB) gene regulatory network. We developed a high-throughput system based on ChIP-Seq for mapping transcription factor (TF) binding, and assayed genome-wide expression following induction of each TF.  Using this method we report on the DNA binding and transcriptional regulatory profile of ~80% of all predicted MTB DNA binding proteins (>150 genes).  We identify many strong candidate interactions for direct transcriptional regulation associated with DNA binding; however, we also note significant DNA binding that cannot be linked directly with transcriptional control.  We propose a model in which TFs act on a spectrum from specific local control of gene expression to widespread binding with little or no direct impact on proximal genes, and suggest that many prokaryotic TFs bind DNA prolifically yet still home to and directly regulate a limited number of targets.  This work updates current concepts of prokaryotic transcriptional control and also should form the basis for iterative rounds of modeling, prediction and refinement in pursuit of badly needed new TB therapies.