John T. Lis

Barbara McClintock Professor of Molecular Biology & Genetics. Using Drosophila heat shock genes as a model, helped define the nature of eukaryotic transcriptional promoters and developed novel methods to uncover the molecular details of transcriptional regulation. Identified rules governing regulatory interactions of trimeric transcription factor HSF1 with its DNA binding elements and developed multiphoton laser-scanning microscopy to demonstrate the recruitment and dynamics of transcription factors at specific gene loci in living tissue. Characterized a mechanism for chromatin decondensation by HSF and PARP following gene activation. Work on methods of crosslinking Chromatin IP (ChIP) for mapping specific gene regulatory proteins on DNA in vivo now common. Used his UV-Chip and nuclear run-on assays to demonstrate that RNA polymerase II is paused on the promoters of uninduced heat shock genes, and that progression to a productively elongating state is a rate-limiting and highly regulated step in transcription. Work to develop a highly sensitive, genome-wide nuclear run-on assay (GRO-seq) further demonstrated that promoter pausing is general among metazoans and plays a role in the regulation of nearly half of all genes in the human genome. Developed strategies for inhibiting specific factor interactions in vivo using RNA aptamers to probe mechanisms of transcription regulation.