Ph.D.,University of California, Berkeley
Postdoctoral Research: Rockefeller University
Lab website: http://lewislab.discovery.wisc.edu/
Address: 2174 Wisconsin Institute for Discovery
Telephone: 608- 316-4388
Department: Biomolecular Chemistry
Epigenetic Mechanisms in Development and Cancer
Chromatin Biology, Disease Biology, Development, Human and Mouse
Chromatin Dynamics in Development and Cancer
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.
• Jayaram H, Hoelper D, Jain SU, Cantone N, Lundgren SM, Poy F, Allis CD, Cummings R, Bellon S, Lewis PW.
S-adenosyl methionine is necessary for inhibition of the methyltransferase G9a by lysine 9 to methionine mutations in histone H3.
Proc Natl Acad Sci. 2016 May 31;113(22):6182-7
• 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.
Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape.
Science. 2016 May 13;352(6287):844-9
• Brown ZZ, Muller MM, Lewis PW, Muir TW.
Targeted Histone Peptides: Insights into the Spatial Regulation of the Methyltransferase PRC2 using a Surrogate of Heterotypic Chromatin.
Angewante Chemie. 2015 May 26;54(22):6457-61
• Noh KM*, Maze I*, Zhao D, Xiang B, Wenderski W, Lewis PW, Shen L, Li H, Allis CD.
ATRX tolerates activity-dependent histone H3 “methyl/phos switching” to maintain repetitive element silencing in neurons.
Proc Natl Acad Sci. 2015 Jun 2;112(22):6820-7
• Funato K, Major T, Lewis PW, Allis CD, Tabar V
Human ESC-based modeling of pediatric gliomas by K27M mutation in histone H3.3 variant.
Science. 2014 Dec 19;346(6216):1529-33
• Venneti S, Santi M, Felicella MM, Tarilin D, Phillips JJ, Sullivan LM, Martinez D, Perry A, Lewis PW, Thompson CB, Judkins AR.
A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas.
Acta Neuropathol. 2014 Nov;128(5):743-53
• Becht D, Gielen GG, Korshunov A, Pfister SM, Rousso C, Faury D, Fiset PO, Benlimane N, Lewis PW, Lu C, Allis CD, Kieran MW, Ligon KL, Peitsch T, Ellezam B, Albrecht S, Jabado N.
Specific detection of methionine 27 mutation in histone H3 variants (H3K27M) in fixed tissue from high-grade astrocytomas.
Acta Neuropathol. 2014 Nov;128(5):733-41
• Brown ZZ*, Muller MM*, Jain SU, Allis CD, Lewis PW, Muir TW.
Strategy for ‘detoxification’ of a cancer-derived histone mutant based on mapping its interaction with methyltransferase PRC2.
J Am Chem Soc. 2014 Oct 1;136(39):13498-501
• 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 PKC, Huang A, Taylor KR, Mackay A, Bendel AE, Nazarian J, Fangusaro JR, Karajannis M, 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.
Comprehensive genomic analysis of diffuse intrinsic pontine gliomas unravels three molecular subgroups and a novel cancer driver ACVR1
Nat Genet. 2014 May;46(5):451-6
• Lewis PW and Allis CD
Poisoning the ‘histone code’ in pediatric gliomagenesis.
Cell Cycle. 2013 Oct 15;12(20):3241-2
• Black JC*, Manning AL*, Van Rechem C*, Kim J*, Ladd B, Cho J, Pineda CM, Murphy N, Daniels DL, Montagna C, Lewis PW, Glass K, Allis CD, Dyson NJ, Getz G, Whetstine JR
KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors.
Cell. 2013 August 1;154(1-15).
• Lewis PW, Muller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, Garcia B, Muir TW, Becher OJ, Allis CD
Inhibition of PRC2 methyltransferase activity by a gain-of-function H3 mutation in Pediatric Glioblastoma.
Science. 2013 May 17;340(614):857-61.
• Elsasser SJ*, Huang H*, Lewis PW, Chin JW, Allis CD, Patel DJ
DAXX envelops a histone H3.3-H4 dimer for H3.3-specific recognition.
Nature. 2012 Nov 22;491(7425):560-5.
• Iwase S, Xian B, Ghos, Rent T, Lewis PW, Cochrane JC, Allis CD, Picketts DJ, Patel DJ, Li H, Shi Y.
ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome.
Nat Struct Mol Biol. 2011 Jun 12;18(7):769-76.
• Elsasser SJ, Allis CD, Lewis PW
New epigenetic drivers of cancers.
Science. 2011 Mar 4;331(6021):1145-6.
• Banaszynski LA*, Allis CD, Lewis PW*
Histone variants in metazoan development.
Dev Cell. 2010 Nov 16; 19:(5) 662-74.
• Lewis PW*, Elsasser SJ*, Noh KM, Stadler SC, Allis CD
The H3.3-specific histone chaperone Daxx cooperates with ATRX in replication-independent chromatin assembly at telomeres.
Proc Natl Acad Sci USA. 2010 Aug 10;107(32):14075-80
• Goldberg AD, Banaszynski LA*, Noh KM*, Lewis PW, Elsaesser SJ, Stadler S, Dewell S, Law M, Guo X, Li X, Wen D, Chapgier A, DeKelver RC, Miller JC, Lee YL, Boydston EA, Holmes MC, Gregory PD, Greally JM, Rafii S, Yang C, Scambler PJ, Garrick D, Gibbons RJ, Higgs DR, Cristea IM, Urnov FD, Zheng D, Allis CD
Distinct factors control histone variant H3.3 localization at specific genomic regions.
Cell. 2010 Mar 5;140(5):678-91.
* authors contributed equally to this work