Peter W. Lewis

Associate Professor

plewis@discovery.wisc.edu

(608) 316-4388

2174 Wisconsin Institute for Discovery (WID)
330 N. Orchard St. Madison, WI 53715

Peter Lewis

Education

• 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

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’). 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.

Publications of Note

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• Klein BJ, Krajewski K, Restrepo S, Lewis PW, Strahl BD, Kutateladze TG (2018) Recognition of cancer mutations in histone H3K36 by epigenetic writers and readers. Epigenetics :1-10

• Hoelper D, Huang H, Jain AY, Patel DJ, Lewis PW (2017) Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX. Nat Commun 8(1):1193 (PMC5662737

• Papillon-Cavanagh S, Lu C, Gayden T, Mikael LG, Bechet D, Karamboulas C, Ailles L, Karamchandani J, Marchione DM, Garcia BA, Weinreb I, Goldstein D, Lewis PW, Dancu OM, Dhaliwal S, Stecho W, Howlett CJ, Mymryk JS, Barrett JW, Nichols AC, Allis CD, Majewski J, Jabado N (2017) Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nat. Genet. 49(2):180-185 (PMC5549104)

• Paul PK, Rabaglia ME, Wang CY, Stapleton DS, Leng N, Kendziorski C, Lewis PW, Keller MP, Attie AD (2016) Histone chaperone ASF1B promotes human β-cell proliferation via recruitment of histone H3.3. Cell Cycle 15(23):3191-3202 (PMC5176155)

• Bayliss J, Mukherjee P, Lu C, Jain SU, Chung C, Martinez D, Sabari B, Margol AS, Panwalkar P, Parolia A, Pekmezci M, McEachin RC, Cieslik M, Tamrazi B, Garcia BA, La Rocca G, Santi M, Lewis PW, Hawkins C, Melnick A, David Allis C, Thompson CB, Chinnaiyan AM, Judkins AR, Venneti S. (2016) Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas. Sci Transl Med. 8(366): 366ra161

• Lu C, Jain SU, Hoelper D, Bechet D, Molden RC, Ran L, Murphy D, Venneti S, Hameed M, Pawel BR, Wunder JS, Dickson BC, Lundgren SM, Jani KS, De Jay N, Papillon-Cavanagh S, Andrulis IL, Sawyer SL, Grynspan D, Turcotte RE, Nadaf J, Fahiminiyah S, Muir TW, Majewski J, Thompson CB, Chi P, Garcia BA, Allis CD, Jabado N, Lewis PW (2016) Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 352(6287):844-9 (PMC4928577)

• Jayaram H, Hoelper D, Jain SU, Cantone N, Lundgren SM, Poy F, Allis CD, Cummings R, Bellon S, Lewis PW (2016) S-adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3. Proc. Natl. Acad. Sci. U.S.A. 113(22):6182-7 (PMC4896705)

• Noh KM, Maze I, Zhao D, Xiang B, Wenderski W, Lewis PW, Shen L, Li H, Allis CD (2015) ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons. Proc. Natl. Acad. Sci. U.S.A. 112(22):6820-7 (PMC4460490)

• Brown ZZ, Müller MM, Kong HE, Lewis PW, Muir TW (2015) Targeted Histone Peptides: Insights into the Spatial Regulation of the Methyltransferase PRC2 by using a Surrogate of Heterotypic Chromatin. Angew. Chem. Int. Ed. Engl. 54(22):6457-61 (PMC4617617)

• Funato K, Major T, Lewis PW, Allis CD, Tabar V (2014) Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science 346(6216):1529-33 (PMC4995593)

• Venneti S, Santi M, Felicella MM, Yarilin D, Phillips JJ, Sullivan LM, Martinez D, Perry A, Lewis PW, Thompson CB, Judkins AR (2014) A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas. Acta Neuropathol. 128(5):743-53 (PMC4201755)

• Bechet D, Gielen GG, Korshunov A, Pfister SM, Rousso C, Faury D, Fiset PO, Benlimane N, Lewis PW, Lu C, David Allis C, Kieran MW, Ligon KL, Pietsch T, Ellezam B, Albrecht S, Jabado N (2014) Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas. Acta Neuropathol. 128(5):733-41 (PMC4201745)

• Brown ZZ, Müller MM, Jain SU, Allis CD, Lewis PW, Muir TW (2014) Strategy for “detoxification” of a cancer-derived histone mutant based on mapping its interaction with the methyltransferase PRC2. J. Am. Chem. Soc. 136(39):13498-501 (PMC4183613)

• Judkins AR, Venneti S, Santi M, Felicella MM, Sullivan LM, Dolgalev I, Martinez D, Perry A, Lewis PW, Allis DC, Thompson CB (2014) Histopathologic evaluation of h3k27me3 is a prognostic biomarker for pediatric glioblastomas. Neuro-oncology 16 Suppl 3:iii29-iii30 (PMC4144571)

• Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, Morrison A, Lewis PW, Bouffet E, Bartels U, Zuccaro J, Agnihotri S, Ryall S, Barszczyk M, Chornenkyy Y, Bourgey M, Bourque G, Montpetit A, Cordero F, Castelo-Branco P, Mangerel J, Tabori U, Ho KC, Huang A, Taylor KR, Mackay A, Bendel AE, Nazarian J, Fangusaro JR, Karajannis MA, Zagzag D, Foreman NK, Donson A, Hegert JV, Smith A, Chan J, Lafay-Cousin L, Dunn S, Hukin J, Dunham C, Scheinemann K, Michaud J, Zelcer S, Ramsay D, Cain J, Brennan C, Souweidane MM, Jones C, Allis CD, Brudno M, Becher OJ, Hawkins C. (2014) Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations Nat. Genet. 5(46):451-6 (PMC3997489)