Abstract Detail

Gene regulatory networks in fungal development and morphogenesis - towards fungal evo-devo

Frazer, Corey [1], Staples, Mae [2], Yim, Yoori [3], Hirakawa, Matthew [4], Dowell, Maureen [2], Hernday, Aaron [5], Fawzi, Nicolas [4], Finkelstein, Ilya [3], Bennett, Richard [6].

Transcription Factors Regulate Fungal Cell Fate by Assembling into Phase-Separated Condensates at Specialized Enhancers.

Candida albicans is a pathobiont of humans, frequently found colonizing the gastrointestinal tract but also able to cause mucosal and systemic disease. This yeast is known to undergo a reversible and heritable switch between two cell states termed “white” and “opaque”. The two cell states exhibit multiple differences including their physical appearance, their competence to undergo sexual mating and in their interactions with immune cells. A complex network of 8 or more transcription factors (TFs) regulates the white-opaque switch, and yet how these TFs coordinate to define cell programming is unknown. Here, we reveal that most white-opaque TFs contain prion-like domains (PrLDs) that are intrinsically disordered domains associated with the ability to undergo liquid-liquid phase separation (LLPS). This phenomenon relates to the ability of proteins in solution to demix into a protein-dense droplet state that is in equilibrium with a more dilute surrounding phase. To determine if Candida TFs can undergo LLPS, we purified key white-opaque TFs and found that they readily phase separate into liquid or gel-like condensates in vitro. Using single molecule “DNA curtain” assays, Candida TFs can form condensates on DNA that can then recruit other TFs to these droplets. We show that C. albicans TFs can co-phase separate in eukaryotic cells and can co-recruit RNA polymerase II to these condensates. Mutational analysis of TFs showed that modulation of LLPS properties dictated white-opaque switching frequencies in Candida cells. We therefore suggest that phase separation of master TFs assembles the transcriptional complexes necessary for target gene expression and determination of cell fate. This model also reveals shared features with the “super-enhancers” that control cell fate in mammals, suggesting a conserved role for this process in eukaryotic transcription.

1 - Brown University, 171 Meeting St, Box G-B6, Providence, RI, 02912-9089, United States
2 - Brown University, 171 Meeting St, Providence, RI, 02912-9089, United States
3 - UT Austin, Molecular Biosciences , Austin, TX, USA
4 - Brown University, Providence, RI, USA
5 - UC Merced, MCB, Merced, CA, USA
6 - Brown University, MMI, 171 Meeting St, Box G-B6, Providence, RI, 02912-9089, United States

Keywords:
gene regulatory network
Fungal diversity
phenotypic plasticity
adaptation.

Presentation Type: Symposium Presentation
Session: SY1, Gene regulatory networks in fungal development and morphogenesis - towards fungal evo-devo
Location: /
Date: Monday, July 19th, 2021
Time: 12:30 PM(EDT)
Number: SY1006
Abstract ID:1119
Candidate for Awards:None