Peter W. Lewis
Credentials: Mechanisms of chromatin assembly, gene silencing, and epigenetic inheritance
Position title: Professor
Email: peter.lewis@wisc.edu
Phone: (608) 263-6599
Address:
Room 6260B Biochemical Sciences Building
440 Henry Mall
Madison, WI 53706
Education
B.S., University of Virginia
Ph.D., University of California, Berkeley (M. Botchan)
Postdoctoral Fellow, The Rockefeller University (C.D. Allis)
Honors & Awards
2013 New Investigator Award, Mary Terese Hartzheim Foundation
2015 Kimmel Scholar Award, Sidney Kimmel Foundation for Cancer Research
2015 Shaw Scientist Award, Greater Milwaukee Foundation
2016 Pew Scholar Award, The Pew Charitable Trusts Program in the Biomedical Sciences
2017 Ride Scholar, The Ride Foundation for Cancer Research
2019 Vilas Faculty Early Career Investigator Award, University of Wisconsin
2021 Innovator Award, Alex’s Lemonade Stand Foundation
2023 Hanns Kuttner Professorship, University of Wisconsin
2023 H.I. Romnes Award, University of Wisconsin
Research Description
Our research group investigates the protein complexes and pathways that establish and maintain heterochromatin, thereby enforcing gene expression programs that define and preserve cell identity. Chromatin couples genomic DNA sequence to covalent modifications of DNA and histone proteins, and this regulatory layer governs access to the genome for transcription and other DNA-templated processes. Stable repression of inappropriate gene expression is required for mammalian development and tissue homeostasis. Disruption of chromatin-based silencing can erode genome integrity and promote tumorigenesis. Although foundational principles of chromatin regulation are well developed, the biochemical mechanisms that initiate heterochromatin, propagate it through cell division, and remodel it with locus specificity remain incompletely defined.
A major focus of the laboratory is Polycomb Repressive Complex 2 (PRC2) and the mechanistic control of histone H3 lysine 27 methylation. We define how PRC2 recruitment and catalytic output are tuned by chromatin context, accessory subunits, and inhibitory regulators, including the H3 K27M oncohistone and the PRC2 inhibitor EZHIP. These mechanistic studies are integrated with functional analyses in mammalian systems, using pediatric glioma models and selected sarcoma models to determine how altered repression reshapes transcriptional programs, lineage decisions, and tumor cell states.
In parallel, we investigate heterochromatin pathways that silence transposable elements and other repetitive genomic regions, including mechanisms involving deposition of histone variant H3.3 by ATRX-DAXX and repression mediated by Human Silencing Hub complexes. Across these themes, we integrate biochemical reconstitution and quantitative mechanistic assays with proteomic, genetic, and genome-wide genomic approaches to connect molecular mechanism to chromatin state, transcriptional output, and biological function.
Representative Publications:
Jain SU, Rashoff AQ, Krabbenhoft SD, Hoelper D, Do TJ, Gibson TJ, Lundgren SM, Bondra ER, Deshmukh S, Harutyunyan AS, Juretic N, Jabado N, Harrison MM, Lewis PW. H3 K27M and EZHIP impede H3K27-methylation spreading by inhibiting allosterically stimulated PRC2. Molecular Cell, 2020 Nov 19;80(4):726-735
Jain SU, Khazaei S, Marchione DM, Lundgren SM, Wang X, Weinberg DN, Deshmukh S, Juretic N, Lu C, Allis CD, Garcia BA, Jabado N, Lewis PW. Histone H3.3 G34 mutations promote aberrant PRC2 activity to drive tumor progression. Proc Natl Acad Sci, 2020 Nov 3;117(44):27354-27364
Peter W. Lewis Publications
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A goldilocks amount of H3K27me3
March 27, 2023