Model-driven mapping of transcriptional networks reveals the circuitry and dynamics of virulence regulation
- Ezekiel John Maier1,2,5,
- Brian Clifton Haynes1,2,5,6,
- Stacey Rae Gish3,
- Zhuo Alex Wang3,
- Michael Leszek Skowyra3,
- Alyssa Liane Marulli3,7,
- Tamara Lea Doering3 and
- Michael Richard Brent1,2,4
- 1Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, Missouri 63108, USA;
- 2Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, USA;
- 3Department of Molecular Microbiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, USA;
- 4Department of Genetics, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, USA
- Corresponding authors: brent{at}wustl.edu, doering{at}wustl.edu
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↵5 These authors contributed equally to this work.
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, midlevel, 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 laboratories focused on specific physiological processes.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.184101.114.
- Received September 9, 2014.
- Accepted January 15, 2015.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
