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

Abstract

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 <i>Mycobacterium tuberculosis</i>, which has greatly impeded our understanding of its pathogenesis and virulence. In this study, we constructed a genome-wide transcription regulatory network of <i>M. tuberculosis</i> 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 (<i>mce1</i>) module, which includes <i>mce1R</i> and the <i>mce1</i> 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 <i>mce1</i> operon was shown to be negatively regulated by the virulence regulator PhoP. These findings provide important new insights into the molecular mechanisms of several <i>mce1</i> module-related hypervirulence phenotypes of the pathogen. Furthermore, a model of <i>mce1</i> module-centered signal circuit for dormancy regulation in <i>M. tuberculosis</i> is proposed and discussed