Peter Lewis

Research Description

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’). 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, animal 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. Part of our research program addresses the function of histone H3.3 with the long-term goal of understanding the role of chromatin variation in the establishment of gene expression patterns that specify cell fate.

Honors

• Ruth L. Kirschstein National Research Service Award 2008
• MTH Foundation Young Investigator Award, 2014
• Kimmel Scholar Award, Sidney Kimmel Foundation for Cancer Research, 2015
• Shaw Scientist Award, Greater Milwaukee Foundation, 2015
• Pew Scholar Award, The Pew Charitable Trusts Program in the Biomedical Sciences, 201

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