The rewiring of transcriptional circuits is a major source of evolutionary novelty. This proposal seeks to determine the detailed molecular mechanisms that underlie transcriptional rewiring using unicellular yeasts as a model system. The strategy is based on direct experimentation in three yeasts2Saccharomyces cerevisiae, Kluyveromyces lactis, and Candida albicans2using gene knockout collections, genome wide transcriptional profiling, chromatic immunoprecipitation, and phylogentic comparisons. Circuit comparisons among these three yeasts reveal specific examples of transcriptional rewiring and provide hypotheses for the molecular mechanisms by which the wiring changes occurred. Specific hypotheses will be tested and refined by phylogenetic comparisons of the over 40 sequenced ascomycete genomes and by additional experiments, including the 3resurrection4 and study of ancient proteins in modern yeasts. Prior and ongoing work on the evolution of the well-characterized yeast mating-type circuitry will serve as a guide;additional studies will include the evolution of regulatory circuits controlling metabolic pathways.

Public Health Relevance

A cell carefully regulates the transcription of each one of its many genes. In humans, abnormalities in this complex process (whether inherited or acquired) can lead to many diseases, including a variety of cancers. Transcriptional circuits are the product of billions of years of evolution, and a complete understanding of them must include a consideration of how they arose and how they can change. Plasticity in transcriptional circuitry is well documented, and a deeper understanding of it will provide insights into recognizing and perhaps treating cases where it leads to aberrant physiologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM037049-28
Application #
8586892
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Sledjeski, Darren D
Project Start
1986-08-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
28
Fiscal Year
2014
Total Cost
$327,045
Indirect Cost
$104,295
Name
University of California San Francisco
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Baker, Christopher R; Hanson-Smith, Victor; Johnson, Alexander D (2013) Following gene duplication, paralog interference constrains transcriptional circuit evolution. Science 342:104-8
Homann, Oliver R; Johnson, Alexander D (2010) MochiView: versatile software for genome browsing and DNA motif analysis. BMC Biol 8:49
Mitrovich, Quinn M; Tuch, Brian B; De La Vega, Francisco M et al. (2010) Evolution of yeast noncoding RNAs reveals an alternative mechanism for widespread intron loss. Science 330:838-41
Booth, Lauren N; Tuch, Brian B; Johnson, Alexander D (2010) Intercalation of a new tier of transcription regulation into an ancient circuit. Nature 468:959-63
Homann, Oliver R; Dea, Jeanselle; Noble, Suzanne M et al. (2009) A phenotypic profile of the Candida albicans regulatory network. PLoS Genet 5:e1000783
Holt, Liam J; Tuch, Brian B; Villen, Judit et al. (2009) Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution. Science 325:1682-6
Green, Sarah R; Johnson, Alexander D (2005) Genome-wide analysis of the functions of a conserved surface on the corepressor Tup1. Mol Biol Cell 16:2605-13
Galgoczy, David J; Cassidy-Stone, Ann; Llinas, Manuel et al. (2004) Genomic dissection of the cell-type-specification circuit in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 101:18069-74
Green, Sarah R; Johnson, Alexander D (2004) Promoter-dependent roles for the Srb10 cyclin-dependent kinase and the Hda1 deacetylase in Tup1-mediated repression in Saccharomyces cerevisiae. Mol Biol Cell 15:4191-202
Uhl, M Andrew; Biery, Matt; Craig, Nancy et al. (2003) Haploinsufficiency-based large-scale forward genetic analysis of filamentous growth in the diploid human fungal pathogen C.albicans. EMBO J 22:2668-78

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