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B.A., 1974, Northwestern University, Evanston
Ph.D., 1981, University of Colorado
Regulation of gene expression; chromosome conformation of genes and their 3D nuclear organization; transcriptional response to heat shock
The goal of our NSF- and NIH-funded research 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) in organisms as diverse as baker’s yeast, fruit fly and human. Using ChIP-seq, we have discovered that in the yeast Saccharomyces cerevisiae, Hsf1 binds to the enhancer regions of a core group of 43 genes under all conditions, and another 30-40 more genes in response to thermal stress. Its constitutive binding is enhanced by cooperative interactions with ‘pioneer’ transcription factors and the chromatin remodeling complex RSC. Moreover, Hsf1 acts in concert with Mediator, a coactivator complex, in driving its transcriptional program. Mediator bridges gene-specific activators with RNA polymerase II (Pol II); it has been likened to a computer microprocessor that integrates multiple signals and converts these into an output – highly precise Pol II-mediated transcription. We have obtained evidence that Hsf1 recruits multiple Mediator complexes to the upstream regulatory regions of HSP genes. What the biological significance of multiple Mediator complexes may be is unknown, but under further investigation. Recently, our laboratory made the striking observation that Hsf1-regulated HSP genes undergo profound conformational changes upon their heat-induced transcriptional activation. These genes form chromatin loops between their 5’- and 3’-ends, ‘crumple’ (engage in concerted intragenic contacts) and most strikingly, coalesce into intranuclear foci. Such chromatin contacts strongly correlate with the instantaneous rate of transcription. Genes regulated by alternative transcription factors, even those responsive to heat shock or interposed between HSP genes, do not coalesce, although they do loop and crumple. Remarkably, all three conformational changes that take place at Hsf1-regulated genes – looping, crumpling and coalescence – are evident within 60 sec of heat shock and peak within the first 2.5 min; they begin to dissipate within 10 min and return to background levels by 120 min. Current efforts are directed towards understanding the molecular basis and biological significance of this dynamic and unprecedented phenomenon.
All Publications: PubMed