Dr. David Gross' Research Focus

Major Research Interests:
Chromatin structure; transcriptional silencing; heat shock; yeast genetics; p53.

Our lab uses molecular genetic and biochemical approaches to explore mechanisms of transcriptional regulation in chromatin. We are interested in understanding how stress-responsive genes are rapidly and vigorously induced in response to environmental stimuli. Our previous work has defined a central role for heat shock factor (HSF), master regulator of the cellular stress response, in activating transcription and opening the chromatin of yeast ‘heat shock’ genes. Our current efforts are focused on identifying the enzymatic partners of HSF – the so-called coactivators and corepressors – and characterizing their role in remodeling chromatin and regulating transcription

We are also interested in understanding how silenced chromatin, a specialized, compact form of chromatin, represses gene transcription. We recently made the surprising discovery that silenced chromatin permits the recruitment of positive regulators, including sequence-specific activators, general transcription factors, and RNA polymerase (Pol II) to a gene’s promoter. How it prevents the recruited Pol II from synthesizing full-length transcripts, and how activated HSF overrides heterochromatic repression, are areas of current inquiry.

Finally, we are studying the mechanism by which p53, a human tumor suppressor, regulates its target genes. Mutations in p53 are associated with 50% of all human cancers. We have therefore placed p53 in yeast to investigate the molecular mechanisms of p53 transcriptional activation and the loss of function in oncogenic p53 mutants.

Schematic of HSP82 promoter chromatin, illustrating the accessible structure of the wild-type promoter, which following induction is bound by HSF, TFIID and Pol II. The activated HSP82 promoter is also largely free of histones, in marked contrast to a promoter mutant termed hsp82-HSE1, whose upstream region is assembled into a repressive pair of nucleosomes (shaded green). DNA is symbolized by the black line.