A Genome-Wide Regulator–DNA Interaction Network in the Human Pathogen Mycobacterium tuberculosis H37Rv

Transcription regulation translates static genome information to dynamic cell behaviors, making it central to understand how cells interact with and adapt to their environment. However, only a limited number of transcription regulators and their target genes have been identified in the pathogen Mycobacterium tuberculosis, which has greatly impeded our understanding of its pathogenesis and virulence. In this study, we constructed a genome-wide transcription regulatory network of M. tuberculosis H37Rv using a high-throughput bacterial one-hybrid technique. A transcription factor skeleton network was derived on the basis of the identification of more than 5400 protein–DNA interactions. Our findings further highlight the regulatory mechanism of the mammalian cell entry 1 (mce1) module, which includes mce1R and the mce1 operon. Mce1R was linked to global negative regulation of cell growth, but was found to be positively regulated by the dormancy response regulator DevR. Expression of the mce1 operon was shown to be negatively regulated by the virulence regulator PhoP. These findings provide important new insights into the molecular mechanisms of several mce1 module-related hypervirulence phenotypes of the pathogen. Furthermore, a model of mce1 module-centered signal circuit for dormancy regulation in M. tuberculosis is proposed and discussed.