title: Model-driven mapping of transcriptional networks reveals the circuitry and dynamics of virulence regulation.
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.
authors: Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, Missouri 63108, USA; Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, USA;
authors: Ezekiel J
authors: EJ
authors: Maier
authors: Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, Missouri 63108, USA; Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, USA;
authors: Brian C
authors: BC
authors: Haynes
authors: Department of Molecular Microbiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, USA;
authors: Stacey R
authors: SR
authors: Gish
authors: Department of Molecular Microbiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, USA;
authors: Zhuo A
authors: ZA
authors: Wang
authors: Department of Molecular Microbiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, USA;
authors: Michael L
authors: ML
authors: Skowyra
authors: Department of Molecular Microbiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, USA;
authors: Alyssa L
authors: AL
authors: Marulli
authors: Department of Molecular Microbiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, USA;
authors: Tamara L
authors: TL
authors: Doering
authors: Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, Missouri 63108, USA; Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, Missouri 63130, USA; Department of Genetics, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, USA.
authors: Michael R
authors: MR
authors: Brent
mesh_terms: D000818:Animals; D002874:Chromosome Mapping / Q000379:methods*; D003455:Cryptococcus neoformans / Q000235:genetics / Q000472:pathogenicity; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D053263:Gene Regulatory Networks; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D014157:Transcription Factors / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics*
chemical_list: D005656:Fungal Proteins; D014157:Transcription Factors; D037521:Virulence Factors
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