Peter W. Lewis
Credentials: Chromatin dynamics in cancer
Position title: Associate Professor
Phone: (608) 316-4388
Room 4212A Biochemical Sciences Building
440 Henry Mall
Madison, WI 53706
• B.S., University of Virginia
• Ph.D., University of California, Berkeley (M. Botchan)
• Postdoctoral Fellow, The Rockefeller University (C.D. Allis)
Honors & Awards
• Ruth L. Kirschstein National Research Service Award 2008
• MTH Foundation Young Investigator Award, 2014
• Sidney Kimmel Foundation for Cancer Research Scholar, 2015
• Shaw Scientist Award, Greater Milwaukee Foundation, 2015
• Pew Scholar Award, The Pew Charitable Trusts Program in the Biomedical Sciences, 2016
The human genome is estimated to contain ~20,000 unique genes, and although every gene exists within every cell of the body, only a small fraction of genes are activated in any given cell type. The establishment of cell type-specific gene expression patterns helps define cell identity during differentiation and development. In order to preserve cell identity, lineage-specific gene expression must be maintained, and failure to stably silence genes normally expressed in other lineages has the potential to cause developmental defects or promote diseases such as cancer.
My research program is rooted in the idea that chromatin, the physiologically relevant form of eukaryotic genomes, contains an indexing system, sometimes referred to as a “histone or epigenetic code”, that represents a fundamental regulatory mechanism that operates outside of the DNA sequence itself. Covalent modifications to DNA and histones – the proteins that package our genome – are implicated in the epigenetic regulation of gene expression and the stable maintenance of cell type-specific gene expression patterns and cellular identity.
Current Research Projects:
Chromatin Dynamics and Epigenetic Regulation in Cancer
A growing literature points to altered chromatin structure as a previously unsuspected driver of many human cancers. For example, a remarkably high frequency of pediatric brain and bone cancers harbor monoallelic, gain-of-function mutations in genes encoding histone H3 (collectively referred to as ‘oncohistones’). Given the restricted distribution of H3 mutations in human cancers, I hypothesize that cell lineage is crucial for the ability of these mutant histone proteins to promote tumorigenesis. Therefore, my laboratory is using a combination of biochemical understanding, accurate model generation, and study of human tumor samples to comprehensively understand how H3 mutations mediate tumorigenesis. Our research will provide general insights into how mutations in the chromatin machinery affect downstream chromatin structure and gene expression to drive tumorigenesis.
Histone Variants and Cell Identity
In addition to the canonical histones, mammalian cells possess several histone variants that function in diverse nuclear processes including centromere activity, DNA repair, telomere maintenance, and gene expression. Histone variants, such as H3.3, are enriched at select genomic regions by specific deposition machinery, and contain variant-specific residues and post-translational modifications. These variant-specific attributes allow the cell to generate biochemically unique nucleosomes for the regulation of DNA-templated processes. My previous research suggests a role for the histone variant H3.3 in maintaining normally silenced regions of the genome. However, the function of H3.3 at these regions is not well understood, and many questions remain regarding the mechanisms by which H3.3 contributes to the establishment and maintenance of cellular identity. Part of our research program address these issues and others with the long-term goal of understanding the role of chromatin variation in the establishment of gene expression patterns that specify cell fate.
Perform a customized PubMed literature search for Peter W. Lewis
- Mabin, J.W., P.W. Lewis, D.A. Brow, and H. Dvinge. (2021). Human spliceosomal snRNA sequence variants generate variant spliceosomes. RNA (New York, N.Y.), 27: 1186-1203.