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)
Research Project (R01)
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Molecular Genetics A Study Section (MGA)
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Sledjeski, Darren D
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University of California San Francisco
Schools of Medicine
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United States
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Sorrells, Trevor R; Johnson, Amanda N; Howard, Conor J et al. (2018) Intrinsic cooperativity potentiates parallel cis-regulatory evolution. Elife 7:
Johnson, Alexander D (2017) The rewiring of transcription circuits in evolution. Curr Opin Genet Dev 47:121-127
Dalal, Chiraj K; Johnson, Alexander D (2017) How transcription circuits explore alternative architectures while maintaining overall circuit output. Genes Dev 31:1397-1405
Nocedal, Isabel; Mancera, Eugenio; Johnson, Alexander D (2017) Gene regulatory network plasticity predates a switch in function of a conserved transcription regulator. Elife 6:
Hanson-Smith, Victor; Johnson, Alexander (2016) PhyloBot: A Web Portal for Automated Phylogenetics, Ancestral Sequence Reconstruction, and Exploration of Mutational Trajectories. PLoS Comput Biol 12:e1004976
Sorrells, Trevor R; Booth, Lauren N; Tuch, Brian B et al. (2015) Intersecting transcription networks constrain gene regulatory evolution. Nature 523:361-5
Nocedal, Isabel; Johnson, Alexander D (2015) How Transcription Networks Evolve and Produce Biological Novelty. Cold Spring Harb Symp Quant Biol 80:265-74
Sorrells, Trevor R; Johnson, Alexander D (2015) Making sense of transcription networks. Cell 161:714-23
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

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