Research
We want to understand how genes are regulated. How do cellular and environmental signals toggle transcription regulatory proteins to be on or off, and by what mechanism do they deliver RNA polymerase to genes? By answering this we are better able to understand and fix the mis-regulation that occurs in human diseases. We study how the transcription machinery assembles at promoters and the role that enhancers play in accelerating this assembly. Students use the latest biochemical, genetic, computational, and genomic technologies in yeast and human model systems. A heavy emphasis is placed on elucidating the precise genome-wide organization of regulatory proteins. This includes how sequence-specific transcription factors engage chromatin remodelers like SAGA, SWI/SNF, and Mediator to augment assembly of RNA polymerase II and the general transcription machinery. In support of student projects and collaborations, we develop high-throughput experimental and computational workflows that precisely map where proteins interact with DNA along chromosomes. This provides a structural understanding of the protein-DNA architecture of chromosomes, and has necessitated the development of powerful computational approaches to analyze millions of ChIP-exo/seq and RNA-seq data values. Function is assessed through CRISPR/Cas9-engineered depletion of regulatory proteins, and through biochemical reconstitution of protein/DNA complexes on a genomic scale. One biomedical goal is to identify protein/DNA interactions that correlate with tissue disease and their treatment outcomes so as to develop improved medical diagnostics.
Current Projects:
- Gene regulation
- Epigenome organization
- Machine learning
Bio
Dr. Pugh received his BS from Cornell University in 1983. He then received his PhD in 1987 at the University of Wisconsin – Madison, on the biochemistry of recA genetic recombination with Michael Cox. From 1988-1991, Dr. Pugh was a Searle postdoctoral fellow with Dr. Robert Tjian at the University of California – Berkeley, where he discovered transcriptional coactivators. He was on the Penn State University faculty from 1991-2020, achieving the rank of full professor, and establishing a vibrant research program on biochemical and genomic mechanisms of gene regulation. In 2020, he moved his lab to Cornell University.
Distinctions:
- Former Editor, Molecular and Cellular Biology
- Former Director – Center for Eukaryotic Gene Regulation (Penn State)
- Former Willaman Professor of Molecular Biology (Penn State)
- Former Evan Pugh University Professor (Penn State)
- Fellow AAAS
- Greater Philadelphia Area Professorship (Cornell)
Selected publications:
Badjatia, N., Rossi, M.J., Bataille, A.R., Mittal, C., Lai, W.K.M., and Pugh, B.F. (2021). Acute stress drives global repression through two independent RNA polymerase II stalling events in Saccharomyces. Cell Rep 34, 108640. (PDF)
Rossi, M.J., Kuntala, P.K., Lai, W.K.M., Yamada, N., Badjatia, N., Mittal, C., Kuzu, G., Bocklund, K., Farrell, N., Blanda, T.R., Mairose, J.D., Basting, A.V., Mistretta, K.S., Rocco, D.J., Perkinson, E.S., Kellogg, G.D., Mahony, S., and Pugh, B.F. (2021). A high-resolution protein architecture of the budding yeast genome. Nature, 592, 309-314. (LINK)
Lai, W.K.M., Mariani, L., Rothschild, G., Smith, E.R., Venters, B.J., Blanda, T.R., Kuntala, P.K., Bocklund, K., Mairose, J., Dweikat, S.N., Mistretta, K., Rossi, M.J., James, D., Anderson, J.T., Phanor, S.K., Zhang, W., Shaw, A.P., Novitzky, K., McAnarney, E., Keogh, M.-C., Shilatifard, A., Basu, U., Bulyk, M.L., and Pugh, B.F. (2021). Screening of PCRP transcription factor antibodies in biochemical assays. Genome Res, 31, 1663-1679. (PDF)
Shao D, Kellogg GD, Nematbakhsh A, Kuntala PK, Mahony S, Pugh BF, Lai WKM. (2022). PEGR: a flexible management platform for reproducible epigenomic and genomic research. Genome Biol. 2022;23(1):99. (PDF)
Mittal C, Lang O, Lai WKM, Pugh BF. (2022). An integrated SAGA and TFIID PIC assembly pathway selective for poised and induced promoters. Genes Dev 36: 985-1001. (PDF)