Assistant Professor of Biomolecular Chemistry, Epigenetics
- 330 North Orchard Street
- Madison WI 53715
- Room 2174
- B.S., University of Virginia
- Ph.D., University of California, Berkeley
- Postdoctoral Fellowship, The Rockefeller University
Epigenetic Mechanisms in Development and Cancer
Our lab focuses on elucidating mechanistic principles of epigenetic regulation in biological processes, including mammalian development, oncogenic transformation and tumor progression. Our research approaches span the spectrum from highly purified biochemical systems to proteomic and genomic analyses, as well as genetic techniques.
Mammalian development requires the specification of dozens of unique cell types from a single totipotent cell. While genetically identical, each cell type is able to establish and maintain the unique gene expression profile that gives rise to its cellular identity. To preserve this identity, lineage-specific gene expression must be maintained, and the failure to epigenetically silence genes from other lineages can cause developmental defects or promote tumorigenesis. Epigenetic regulation refers to changes in gene expression or phenotype caused by mechanisms other than changes to the underlying DNA sequence. This regulation is mediated at the level of chromatin, which is principally composed of genomic DNA and intimately associated proteins such as histones. Changes in chromatin structure influence the establishment and maintenance of specific epigenetic states during cell differentiation. Alteration of chromatin structure can occur through chemical modification to DNA or histone proteins, ATP-dependent nucleosome mobilization, association of non-coding RNAs, and the deposition of histone variant proteins. Together with sequence-specific transcription factors, these intersecting mechanisms serve critical roles in animal development as regulators of gene expression and carriers of epigenetic information.
Projects in our lab focus on how histone variants and chromatin modifying machinery contribute to epigenetic states. In addition to the canonical histones, mammalian cells possess several histone variants that function in diverse nuclear processes including centromere activity, DNA repair, meiosis, 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.
Additionally, we explore how mutations in chromatin machinery and misregulation of epigenetic states can contribute to tumorigenesis. Somatic mutations in genes encoding proteins that modify chromatin dynamics frequently contribute to tumorigenesis. Furthermore, mutations in genes encoding histone variants provide direct evidence that alterations of the histones themselves can promote cancer. We recently identified potential mechanisms through which these mutations alter epigenetic states resulting in tumor formation.
•Lewis PW and Allis CD
Poisoning the ‘histone code’ in pediatric gliomagenesis.
Cell Cycle, 2013 September 1.
•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.
•Lewis PW*, Sahoo D*, Geng C*, Bell M, Lipsick JS, Botchan MR
Drosophila Lin-52 acts in opposition to repressive components of the MMB/dREAM complex.
Mol Cell Biol. 2012 Aug;32(16):3218-27.
•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.
•Georlette D, Ahn S, MacAlpine DM, Cheung E, Lewis PW, Beall EL, Bell SP, Speed T, Manak JR, Botchan MR Genomic profiling and expression studies reveal both positive and negative activities for the Drosophila Myb-MuvB/dream complex in proliferating cells.
Genes Dev. 2007 Nov 15;21(22):2880-96.
•Beall EL*, Lewis PW*, Bell M, Rocha M, Jones DL, Botchan MR
Discovery of tMAC: a Drosophila testis-specific meiotic arrest complex paralogous to Myb-MuvB.
Genes Dev. 2007 Apr 15;21(8):904-19.
•Moyer S, Lewis PW, Botchan MR
Isolation of the Cdc45/Mcm2-7/GINS (CMG) complex, a candidate for the eukaryotic DNA replication fork helicase.
Proc Natl Acad Sci USA, 2006 Jul 5;103(27):10236-41.
•Lewis PW, Beall EL, Fleischer TC, Georlette D, Link AJ, Botchan MR
Identification of a Drosophila Myb-E2F2/RBF transcriptional repressor complex.
Genes Dev. 2004 Dec 1;18(23):2929-40.
•Johnson JS, Oshemi YN, Xue Y, Emanuel MR, Lewis PW, Bankovich A, Beyer AL, Engel DA
Adenovirus protein VII condenses DNA, represses transcription, and associates with transcriptional activator E1A.
J Virol. 2004 Jun;78(12):6459-68.
* authors contributed equally to this work