
Professor & Vice Chair
Department of Microbiology and Immunology
Primary Thematic Area
Secondary Thematic Area
Research Summary
Microbial Evolution and Pathogenesis
+1 415 502-7196
- Molecular Biology of Evolution. The gradual rewiring of transcriptional circuits over evolutionary timescales is a major source of the diversity of life on the planet. We study the molecular mechanisms that underlie these rewiring events to understand what it is about transcription circuits that make them highly evolvable. We also study how such changes in circuitry lead to differences in appearance and behavior among species. We carry out this work in a large group of unicellular eukaryotes (the fungi) including the "model" eucaryoteSaccharomyces cerevisiae and the human fungal pathogen Candida albicans. These organisms are approximately as divergent as fish and humans, and we have documented major differences in their transcriptional circuitries. We study the molecular mechanisms through which these changes have occurred and how potential fitness barriers were traversed during these transitions.
- Molecular Biology of Candida albicans. C. albicans is a species of fungus that typically resides asymptomatically in the gastrointestinal tracts of humans and other warm-blooded animals. It is also the most prevalent human fungal pathogen, causing a variety of skin and soft tissue infections in healthy people and more virulent and invasive and disseminated diseases in immunocompromised humans. We study the specific features of C. albicans that allow it to survive in a human mammalian host and to cause disease and how these features evolved under the selective pressure of the host. We study how C. albicans forms biofilms, how it interacts with host cells, how it interacts with other members of the human microflora, and how its transcription circuits and RNA splicing patterns have adapted it for the host. We are especially interested in a process called white-opaque switching, which appears key to C. albicans' ability to thrive in a mammalian host. Switching is epigenetic, producing two distinct types of cells from the same genome; each cell-type is heritable for many generations, and they differ in their appearance, the genes they express, and the host tissues they are most suited for. We study the switching mechanism, as well as the specializations of the two cell types produced from it.
Websites
Publications
Broad susceptibility of Candida auris strains to 8-hydroxyquinolines and mechanisms of resistance.
mBio
Ancient transcriptional regulators can easily evolve new pair-wise cooperativity.
Proceedings of the National Academy of Sciences of the United States of America
Cell-type memory in a single-cell eukaryote requires the continuous presence of a specific transcription regulator.
Proceedings of the National Academy of Sciences of the United States of America
Broad sensitivity of Candida auris strains to quinolones and mechanisms of resistance.
bioRxiv : the preprint server for biology
Evolution of the complex transcription network controlling biofilm formation in Candida species.
eLife
Lineage-specific selection and the evolution of virulence in the Candida clade.
Proceedings of the National Academy of Sciences of the United States of America
A Screen for Small Molecules to Target Candida albicans Biofilms.
Journal of fungi (Basel, Switzerland)
A Set of Diverse Genes Influence the Frequency of White-Opaque Switching in Candida albicans.
G3 (Bethesda, Md.)
Combination of Antifungal Drugs and Protease Inhibitors Prevent Candida albicans Biofilm Formation and Disrupt Mature Biofilms.
Frontiers in microbiology
A Selective Serotonin Reuptake Inhibitor, a Proton Pump Inhibitor, and Two Calcium Channel Blockers Inhibit Candida albicans Biofilms.
Microorganisms
Corrigendum: Genetic Modification of Closely Related Candida Species.
Frontiers in microbiology
Protein-coding changes preceded cis-regulatory gains in a newly evolved transcription circuit.
Science (New York, N.Y.)
A population shift between two heritable cell types of the pathogen Candida albicans is based both on switching and selective proliferation.
Proceedings of the National Academy of Sciences of the United States of America
Genetic Modification of Closely Related Candida Species.
Frontiers in microbiology
The rewiring of transcription circuits in evolution.
Current opinion in genetics & development
Development and regulation of single- and multi-species Candida albicans biofilms.
Nature reviews. Microbiology
Sensitivity of White and Opaque Candida albicans Cells to Antifungal Drugs.
Antimicrobial agents and chemotherapy
How transcription circuits explore alternative architectures while maintaining overall circuit output.
Genes & development
Assessment and Optimizations of Candida albicans In Vitro Biofilm Assays.
Antimicrobial agents and chemotherapy
Sex differences in vascular dysfunction and cardiovascular outcomes: The cardiac, endothelial function, and arterial stiffness in ESRD (CERES) study.
Hemodialysis international. International Symposium on Home Hemodialysis
Identification and Characterization of Wor4, a New Transcriptional Regulator of White-Opaque Switching.
G3 (Bethesda, Md.)
How Transcription Networks Evolve and Produce Biological Novelty.
Cold Spring Harbor symposia on quantitative biology
Destructin-1 is a collagen-degrading endopeptidase secreted by Pseudogymnoascus destructans, the causative agent of white-nose syndrome.
Proceedings of the National Academy of Sciences of the United States of America
An expanded regulatory network temporally controls Candida albicans biofilm formation.
Molecular microbiology
Finding a Missing Gene: EFG1 Regulates Morphogenesis in Candida tropicalis.
G3 (Bethesda, Md.)
Candida albicans Biofilms and Human Disease.
Annual review of microbiology
Anaerobic bacteria grow within Candida albicans biofilms and induce biofilm formation in suspension cultures.
Current biology : CB
Structure of a new DNA-binding domain which regulates pathogenesis in a wide variety of fungi.
Proceedings of the National Academy of Sciences of the United States of America
A histone deacetylase complex mediates biofilm dispersal and drug resistance in Candida albicans.
mBio
How duplicated transcription regulators can diversify to govern the expression of nonoverlapping sets of genes.
Genes & development
Regulatory circuits that enable proliferation of the fungus Candida albicans in a mammalian host.
PLoS pathogens
Following gene duplication, paralog interference constrains transcriptional circuit evolution.
Science (New York, N.Y.)
Structure of the transcriptional network controlling white-opaque switching in Candida albicans.
Molecular microbiology
Identification and characterization of a previously undescribed family of sequence-specific DNA-binding domains.
Proceedings of the National Academy of Sciences of the United States of America
Genetic control of conventional and pheromone-stimulated biofilm formation in Candida albicans.
PLoS pathogens
Candida albicans white and opaque cells undergo distinct programs of filamentous growth.
PLoS pathogens
A conserved transcriptional regulator governs fungal morphology in widely diverged species.
Genetics
Extensive DNA-binding specificity divergence of a conserved transcription regulator.
Proceedings of the National Academy of Sciences of the United States of America
Evolution of yeast noncoding RNAs reveals an alternative mechanism for widespread intron loss.
Science (New York, N.Y.)
Evolution of transcription networks--lessons from yeasts.
Current biology : CB
Temporal anatomy of an epigenetic switch in cell programming: the white-opaque transition of C. albicans.
Molecular microbiology
The transcriptomes of two heritable cell types illuminate the circuit governing their differentiation.
PLoS genetics
Distinct class of DNA-binding domains is exemplified by a master regulator of phenotypic switching in Candida albicans.
Proceedings of the National Academy of Sciences of the United States of America
Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity.
Nature genetics
Genetics and molecular biology in Candida albicans.
Methods in enzymology
White-opaque switching in Candida albicans.
Current opinion in microbiology
An RNA transport system in Candida albicans regulates hyphal morphology and invasive growth.
PLoS genetics
Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution.
Science (New York, N.Y.)
Biofilm matrix regulation by Candida albicans Zap1.
PLoS biology
Phagocytosis of Candida albicans by RNAi-treated Drosophila S2 cells.
Methods in molecular biology (Clifton, N.J.)
Evolution of eukaryotic transcription circuits.
Science (New York, N.Y.)
Interlocking transcriptional feedback loops control white-opaque switching in Candida albicans.
PLoS biology
Computational and experimental approaches double the number of known introns in the pathogenic yeast Candida albicans.
Genome research
Genetics of Candida albicans, a diploid human fungal pathogen.
Annual review of genetics
The role of nutrient regulation and the Gpa2 protein in the mating pheromone response of C. albicans.
Molecular microbiology
Epigenetic properties of white-opaque switching in Candida albicans are based on a self-sustaining transcriptional feedback loop.
Proceedings of the National Academy of Sciences of the United States of America
Identification of Drosophila gene products required for phagocytosis of Candida albicans.
PLoS biology
Transcriptional response of Candida albicans to nitric oxide and the role of the YHB1 gene in nitrosative stress and virulence.
Molecular biology of the cell
Induction of the Candida albicans filamentous growth program by relief of transcriptional repression: a genome-wide analysis.
Molecular biology of the cell
Genome-wide analysis of the functions of a conserved surface on the corepressor Tup1.
Molecular biology of the cell
Nuclear fusion occurs during mating in Candida albicans and is dependent on the KAR3 gene.
Molecular microbiology
Strains and strategies for large-scale gene deletion studies of the diploid human fungal pathogen Candida albicans.
Eukaryotic cell
Genomic dissection of the cell-type-specification circuit in Saccharomyces cerevisiae.
Proceedings of the National Academy of Sciences of the United States of America
Promoter-dependent roles for the Srb10 cyclin-dependent kinase and the Hda1 deacetylase in Tup1-mediated repression in Saccharomyces cerevisiae.
Molecular biology of the cell
Identification and characterization of a Candida albicans mating pheromone.
Molecular and cellular biology
The biology of mating in Candida albicans.
Nature reviews. Microbiology
Haploinsufficiency-based large-scale forward genetic analysis of filamentous growth in the diploid human fungal pathogen C.albicans.
The EMBO journal
Completion of a parasexual cycle in Candida albicans by induced chromosome loss in tetraploid strains.
The EMBO journal
Chromatin remodeling protein Chd1 interacts with transcription elongation factors and localizes to transcribed genes.
The EMBO journal
Ash1 protein, an asymmetrically localized transcriptional regulator, controls filamentous growth and virulence of Candida albicans.
Molecular and cellular biology
Development of Streptococcus thermophilus lacZ as a reporter gene for Candida albicans.
Microbiology (Reading, England)