Major Research Interests:

The goal of our NIH- and NSF-funded research program is to dissect the molecular mechanisms by which the transcription of protein-encoding genes is regulated.  A central focus is the gene-specific activator Heat Shock Factor 1 (Hsf1), master regulator of the eukaryotic heat shock response.  Hsf1 regulates the expression of genes that encode molecular chaperones and other cytoprotective Heat Shock Proteins (HSPs).  We have discovered that in the yeast, Saccharomyces cerevisiae, Hsf1 binds to the enhancer/UAS regions of a core group of ~50 genes whose heat shock-induced transcription is strongly dependent on this protein. Its constitutive binding to a subset of these genes is enhanced by cooperative interactions with ‘pioneer’ transcription factors and chromatin remodeling complexes. Moreover, Hsf1 acts in concert with Mediator, a conserved coactivator complex, in driving its transcriptional program. 

Recently, our laboratory made the striking observation that Heat Shock Protein (HSP) genes under the control of Hsf1 undergo profound conformational changes upon their heat-induced transcriptional activation. These genes form chromatin loops between their 5’- and 3’-ends, engage in concerted intragenic contacts and most strikingly, coalesce into discrete intranuclear foci through both intra- and interchromosomal interactions. Such chromatin contacts strongly correlate with the instantaneous rate of HSP gene transcription and lead to a dramatic restructuring of the yeast genome. Genome restructuring is critically dependent on at least two proteins, DNA-bound Hsf1 and transcriptionally engaged RNA Polymerase II. Genes regulated by alternative transcription factors, even those responsive to heat shock or interposed between HSP genes, do not coalesce. Our data suggest that Hsf1, likely in combination with other factors (currently under investigation), drives its target loci into a phase-separated state whose assembly is highly dynamic and critically required for the robust expression of HSP genes, and by extension, cell survival under conditions of acute thermal stress.