Evolution of stress response gene regulatory network in a commensal and opportunistic yeast pathogen

The National Institute of General Medical Sciences awarded The University of Iowa $393,275 on September 2, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to study the evolution of stress response gene regulatory networks in commensal and opportunistic yeast pathogens, with performance through August 31, 2031, at Iowa City, Iowa.

The research investigates how signaling and transcriptional circuits evolve at genetic and molecular levels, using genetically related but ecologically diverse yeasts in the Saccharomycotina subphylum as a model system. The work aims to identify key genetic changes in stress response networks within pathogenic yeasts and to understand host adaptation mechanisms. Prior work supported under NIGMS's Maximizing Investigators' Research Award (MIRA) program revealed a novel mode of transcription factor evolution through divergence in intrinsically disordered regions, discovered an acquired stress resistance trait in the pathogenic yeast Candida glabrata (phosphate limitation enhances survival threefold to tenfold against severe hydrogen peroxide challenge), and documented repeated expansion of an adhesin family across multiple pathogenic lineages. The investigator's laboratory also optimized a fluorescence dye-based survival assay for diverse yeast species that is fast and scalable for use in subsequent work.

Abstract

Gene regulatory evolution is rampant and widely recognized as a major driver for phenotypic divergence. Yet our understanding of how the signaling and transcriptional circuits evolve at a genetic and molecular level is still very limited. Existing knowledge is largely derived from studies of developmental networks and focused on the CIS-regulatory elements, precluding a general understanding. Stress response is crucial for survival and needs to evolve as organisms adapt to a new environment. Studying the evolution of stress responses thus serves as a promising model to achieve the above goal. My lab uses a group of genetically related and yet ecologically diverse yeasts in the saccharomycotina subphylum as a model clade, which includes multiple, independently derived human opportunistic pathogens. Stress response evolution is expected to be a key component in host adaptation, and thus dissecting its evolution between related pathogens and low pathogenic species can offer critical insight into how novel pathogens evolved. Our long term goal is to broaden and deepen our understanding of gene regulatory evolution, and to identify key genetic changes in the stress response networks in pathogenic yeasts. Our mira funded work in the past five years revealed a novel mode of transcription factor (TF) evolution in CO-TF dependence through divergence in the intrinsically disordered regions (idrs). We also discovered a novel acquired stress resistance (ASR) trait in the pathogenic yeast c. Glabrata but absent in the related s. Cerevisiae, where phosphate limitation enhances the survival by 3-10 fold to a severe H2O2 challenge. We also revealed repeated expansion of an adhesin family in multiple pathogenic lineages and optimized a fluorescence DYE based survival assay for diverse yeast species that is fast and scalable. Our specific goals in the next five years are to 1) determine the mechanism and evolution of idrs and pioneer factor activities in TFS driving gene regulatory evolution; 2) dissect the signaling and transcriptional circuits behind the divergent ASR in c. Glabrata and s. Cerevisiae; 3) determine the evolutionary pattern of all adhesin families ("adhesinome") in pathogenic yeast clades. Investigating IDR evolution and pioneer factor activities in TFS and dissecting the rewiring of ASR signaling networks are conceptually novel. The proposed work is also innovative in the wide range of techniques used, including single-cell fluorescence reporter, in-vitro nucleosomal DNA binding, transposon-insertion screen, and chemical genetic perturbation of signaling pathways. This research is significant in that IT will reveal fundamental principles governing TF evolution and gene regulatory network while providing novel insight into the genetic adaptation in pathogenic yeasts in their stress response network and adhesin gene repertoire.