In order to create a map of how TB genes are regulated, researchers led by Gary K. Schoolnik, Ph.D., at the Stanford Medical School, David Sherman, Ph.D., of Seattle BioMed and James E. Galagan, Ph.D., of Boston University and the Broad Institute, turned to technologies that identified the key players in the system. Using ChIP-Seq, a method to analyze how proteins interact with DNA, they identified where 50 of TB's regulatory transcription factors bound to DNA, thereby providing the wiring diagram of genetic connections.
Though this kind of linking of transcription factors to genes had been done piecemeal in the past, Sherman explains, this is the first time that such a comprehensive study has been done all at once. "Nobody has ever done ChIP-Seq for every transcription factor in an organism," he says. "This is a far more global view of one organism's wiring than anyone has ever achieved before."
Creating a road map for future interventions
Because the regulatory map yields a systems view of how different genes in the TB bacterium interact, it will be useful to virtually everyone who studies TB, says Sherman. The network provides key insights into the relative regulatory importance of some genes, and yields unexpected relationships between others.
"Everyone who studies TB can now look at this wiring diagram and gain a better understanding of how their favorite genes relate in a larger context," he says. "Suddenly, we can see how different areas connect, in intimate and important detail."
Though this map is the most comprehensive to date, Sherman and his colleagues plan to fill it out even further by incorporating the sequences of the remaining transcription factors and their relationship to the TB genome. The map will eventually provide a window into how targeted drugs or immunological interventions could interfere with TB's ability to survive in the host, adding a critical weapon to the fight again
|Contact: Hannah Krakauer|
Seattle Biomedical Research Institute