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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Genetics A Study Section (MGA)
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Reddy, Michael K
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University of California San Francisco
Schools of Medicine
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Sorrells, Trevor R; Booth, Lauren N; Tuch, Brian B et al. (2015) Intersecting transcription networks constrain gene regulatory evolution. Nature 523:361-5
Sorrells, Trevor R; Johnson, Alexander D (2015) Making sense of transcription networks. Cell 161:714-23
Nocedal, Isabel; Johnson, Alexander D (2015) How Transcription Networks Evolve and Produce Biological Novelty. Cold Spring Harb Symp Quant Biol 80:265-74
Howard, Conor J; Hanson-Smith, Victor; Kennedy, Kristopher J et al. (2014) Ancestral resurrection reveals evolutionary mechanisms of kinase plasticity. Elife 3:
Baker, Christopher R; Hanson-Smith, Victor; Johnson, Alexander D (2013) Following gene duplication, paralog interference constrains transcriptional circuit evolution. Science 342:104-8
Baker, Christopher R; Booth, Lauren N; Sorrells, Trevor R et al. (2012) Protein modularity, cooperative binding, and hybrid regulatory states underlie transcriptional network diversification. Cell 151:80-95
Baker, Christopher R; Tuch, Brian B; Johnson, Alexander D (2011) Extensive DNA-binding specificity divergence of a conserved transcription regulator. Proc Natl Acad Sci U S A 108:7493-8
Homann, Oliver R; Johnson, Alexander D (2010) MochiView: versatile software for genome browsing and DNA motif analysis. BMC Biol 8:49
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Li, Hao; Johnson, Alexander D (2010) Evolution of transcription networks--lessons from yeasts. Curr Biol 20:R746-53

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