Model-driven mapping of transcriptional networks reveals the circuitry and dynamics of virulence regulation
- Ezekiel John Maier,
- Brian C Haynes,
- Stacey Rae Gish,
- Zhuo Alex Wang,
- Michael Leszek Skowyra,
- Alyssa Liane Marulli,
- Tamara Lea Doering and
- Michael R Brent1
- ↵* Corresponding author; email: brent{at}cs.wustl.edu
Abstract
Key steps in understanding a biological process include identifying genes that are involved and determining how they are regulated. We developed a novel method for identifying transcription factors (TFs) involved in a specific process and used it to map regulation of the key virulence factor of a deadly fungus, its capsule. The map, built from expression profiles of 41 TF mutants, includes 20 TFs not previously known to regulate virulence attributes. It also reveals a hierarchy comprising executive, mid-level, and 'foreman' TFs. When grouped by temporal expression pattern, these TFs explain much of the transcriptional dynamics of capsule induction. Phenotypic analysis of TF deletion mutants revealed complex relationships among virulence factors and virulence in mice. These resources and analyses provide the first integrated, systems level view of capsule regulation and biosynthesis. Our methods dramatically improve the efficiency with which transcriptional networks can be analyzed, making genomic approaches accessible to labs focused on specific physiological processes.
- Received September 9, 2014.
- Accepted January 15, 2015.
- Published by Cold Spring Harbor Laboratory Press
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