In slide at the top of page

Hsf1 remodels budding yeast genome architecture

  • Foreground: Schematic depicting an Hsf1 trimer (yellow) bound to a Heat Shock Element (HSE), activating transcription of an HSP gene. RNA Pol II in the background (pink) leaves the pre-initiation complex (pink, red, and green protein complex). Activation of Hsf1 is accompanied by formation of Hsf1 biomolecular condensates (represented as spheres of different sizes, yellow and orange outlines). HSP genes engage in coalescence (looping DNA, green and blue ribbons) and meet at Hsf1 condensates.
  • Media: Gouache over mixed media paper.
woman standing with hands folded in front of her

Linda S. Rubio, PhD

BS, Biology, LSU-Alexandria, 2015
PhD, Biochemistry and Molecular Biology, LSUHS, 2023

Inducible transcriptional activation of eukaryotic genes has been correlated with the formation of biomolecular condensates, promoted by Gene Specific Transcription Factors (GSTFs). Biomolecular condensates in this context are formed by the liquid-liquid phase separation (LLPS) capabilities of GSTFs’ activation domains, which are largely unstructured. These condensates recruit coactivators and transcriptional machinery, along with RNA polymerase (Pol II). The LLPS of the GSTFs and associated machinery act as crucibles to increase the dwell time of a GSTF over target loci and to induce high levels of transcriptional activity in response to stimuli, while limiting the inward diffusion of unneeded molecules into the condensate.

A recent example of this phenomenon is represented by Heat Shock Factor 1 (Hsf1), which forms condensates in response to heat shock in human and budding yeast cells. In budding yeast, the formation of Hsf1 condensates goes beyond gene activation: Hsf1 target genes engage in physical interactions (coalescence) in conjunction with their transcriptional activation, as seen both by microscopy and ligation-proximity assays. These heat shock-induced interactions are strictly dependent on Hsf1 and Pol II.

In my project, I am investigating the response of Hsf1 in yeast cells subjected to ethanol stress. Using live cell fluorescence microscopy, I have observed rapid formation of Hsf1 condensates in cells exposed to ethanol. However, these condensates exhibit properties that differ from those formed in response to heat shock: Pol II recruitment is severely delayed and Hsf1 condensates are long-lasting (present even after 4 h of ethanol stress vs. dissipation within 30 min in response to heat). Yet intergenic interactions between Heat Shock Response genes take place almost as rapidly as in heat-shocked cells, despite a substantial delay in transcription in ethanol-stressed cells. These results highlight the heterogeneity in the activity of a transcription factor in response to different stimuli, suggesting that an intricate mechanism is employed by Saccharomyces cerevisiae in its response to disparate environmental stresses.

Rubio Lab image

HSP genes engage in physical interactions kinetically uncoupled from their transcription in cells exposed to ethanol stress

Working model depicting the response of  Hsf1-regulated genes in response to either heat shock (left) or ethanol stress (right).

Heat shock exposure (left) induces rapid formation of Hsf1 and Pol II biomolecular condensates that correlate with high levels of Hsf1-driven HSP mRNA production (gray glow emerging from the HSP genes) and physical interaction between HSP genes.

Ethanol stress (right) induces formation of Hsf1 condensates with lower density than heat shock. These condensates are deficient in recruitment of Pol II, leading to reduced HSP mRNA production, particularly early in the response (gray glow from emerging from the HSP genes). Despite their delayed and muted transcription, HSP genes interact with kinetics and frequencies similar to those seen under heat shock.

Linda S. Rubio Research

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Dr. Lucy Robinson, LSU Health Shreveport

Lucy Robinson, PhD
Associate Professor of Biochemistry and Molecular Biology, Graduate Program Director