Welcome to the

Pfeifer Laboratory

Overview

Epigenetic Pathways in Disease

The Pfeifer Lab studies how epigenetic processes contribute to the etiology of cancer and potentially to other human diseases. One major research direction is aimed at understanding the mechanisms of DNA methylation and demethylation, two antagonistic processes that are disrupted in disease leading to aberrant cell function and malignant transformation. One major DNA demethylation pathway involves enzymatic oxidation of 5-methylcytosine (5mC) by TET dioxygenases leading to the formation of 5-hydroxymethylcytosine (5hmC) and additional oxidation products that are removed by DNA repair. The lab investigates how the function of TET proteins is controlled. The DNA base 5hmC is particularly abundant in neuronal cells. Ongoing studies have shown that the oxidation of 5mC is critical for the differentiation and migration of cortical neurons and that this process may help maintain long-term functionality of these postmitotic cells in the mammalian brain.

Our Impact

We’re raising thousands to save millions.

We’re turning hope into action for the millions of people around the world affected by diseases like cancer and Parkinson’s. Find out how you can help us make a difference.

  • 171 studies published from Nov. 1, 2020 to Oct. 1, 2021
  • 68 studies in high-impact journals from Nov. 1, 2020-Oct. 1, 2021
  • 41 clinical trials launched

Gerd Pfeifer, Ph.D.

Professor, Department of Epigenetics

Areas of Expertise

Epigenetics, DNA methylation, 5-hydroxymethylcytosine, mutagenesis

Biography

Dr. Gerd Pfeifer earned his Ph.D. in biochemistry from Goethe University in Frankfurt, Germany. Following a postdoctoral fellowship at the University of Frankfurt Medical School, he joined the Beckman Research Institute at City of Hope in Duarte, Calif. in 1988. In 1993, he became full member of City of Hope Comprehensive Cancer Center and, in 1999, he was promoted to Professor of Biology at Beckman Research Institute. He also served as Program Leader for the City of Hope’s Programs in DNA Damage and Repair, Cancer Biology, and Lung Cancer; as chair of the Department of Biology (2001–2008); and as chair of the Department of Cancer Biology (2008–2012). At City of Hope, he was the Lester M. and Irene C. Finkelstein Chair in Biology (2008–2014). He joined VAI in 2014 as a Professor in the Department of Epigenetics. In 2015, he was elected as Fellow of the American Association for the Advancement of Science (AAAS).

Project 1

DNA Methylation and Cancer

One of the lab’s primary projects is studying the mechanisms and biological significance of CpG island hypermethylation in cancer by investigating the molecular pathways that lead to DNA methylation changes in tumors. The lab’s hypothesis is that specific factors such as carcinogenic agents, oncogene activation, inflammation, mechanisms related to the Polycomb repression complex, and imbalances between methylation and demethylation pathways drive the common event of CpG island methylation in tumors.

Project 2

The Role of 5-Methylcytosine Oxidation in Development and Disease

The Pfeifer Lab has previously found that 5hmC is extremely rare in human cancer; therefore, this knowledge could lead to new biomarkers for malignant cancer. The lab hypothesizes that defects in 5-methylcytosine (5mC) oxidation are responsible for different DNA methylation patterns in tumors and, potentially, other diseases. To test this hypothesis, the Pfeifer Lab has established and used methodology for genome-wide mapping and precise quantification of 5mC and 5hmC, with the goal of determining genomic distribution of 5hmC in normal tissues, in malignant tumors and in disease states. To this end, the lab focuses on solid tumors and investigates the role of the TET proteins that catalyze the conversion of 5mC to 5hmC and additional oxidized bases. The lab conducts basic mechanistic studies of TET and TET-associated proteins, along with their regulation, abnormalities in cancer and their roles in cell differentiation and CpG island integrity.

Project 3

Origins of Mutations in Cancer

Cancer genomes are characterized by large numbers of mutations with different mutational signatures found in different tumor types. With the exception of sunlight-induced skin cancers and smoking-associated lung cancers, there are only a few other cases where the mechanisms of the mutations’ origin are understood. The lab focuses on a few such cancer types that include liver cancer and esophageal cancer, for which a mechanism based on the mutation data can be proposed. Towards analyzing novel mechanisms of mutagenesis, the Pfeifer Lab has developed new, highly sensitive methodology to characterize specific DNA damage at every position in the human genome.

SELECTED PUBLICATIONS

For a full list of Dr. Pfeifer’s publications, please visit PubMed.

Meng Y, Wang G, He H, Lau KH, Hurt A, Bixler BJ, Parham A, Jin SG, Zu X, Vasquez KM, Pfeifer GP, Szabó PE. 2022. Z-DNA is remodelled by ZBTB43 in prospermatagonia to safeguard the germline and epigenome. Nat Cell Biol.

Jin SG, Meng Y, Johnson J, Szabó PE, Pfeifer GP. 2022. Concordance of hydrogen peroxide-induced 8-oxoguanine patterns with two cancer mutation signatures of upper GI tract tumorsSci Adv 8(2).

Pfeifer GP. 2022. The ups and downs of DNA methylation: an interview with Gerd Pfeifer. Epigenomics 14(6):339–343.

Cui W, Huang Z, Pfeifer GP. 2022. Lack of major genome-wide DNA methylation changes in succinate-treated human epithelial cells. Int J Mol Sci 23(10):5663.

Pfeifer GP. 2021. DNA repair in neurons and its possible link to the epigenetic machinery at enhancers. Epigenomics 13(12): 913–917.

Kim SI, Pfeifer GP. 2021. The epigenetic DNA modification 5-carboxylcytosine promotes high levels of cyclobutane pyrimidine dimer formation upon UVB irradiation. Gen Insta Dis 2(1):59–69.

Jin SG, Pettinga D, Johnson J, Li P, Pfeifer GP. 2021. The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing. Sci Adv 7(31):eabi6508.

Huang Z, Yu J, Johnson J, Jin SG, Pfeifer GP. 2021. Purification of TET proteins. Methods Mol Biol 2272:225–237.

Huang Z, Yu J, Cui W, Johnson BK, Kim K, Pfeifer GP. 2021. The chromosomal protein SMCHD1 regulates DNA methylation and the 2c-like state of embryonic stem cells by antagonizing TET proteins. Sci Adv 7(4): eabb9149.

Huang Z, Meng Y, Szabó PE, Kohli RM, Pfeifer GP. 2021. High-resolution analysis of 5-hydroxymethylcytosine by TET-assisted bisulfite sequencing. Methods Mol Biol 2198:321–331.

Himadewi P, Wang XQD, Feng F, Gore H, Liu Y, Yu L, Kurita R, Nakamura Y, Pfeifer GP, Zhang X. 2021. 3’HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression. eLife 10:e70557.

Pfeifer GP. 2020. Smoke signals in the DNA of normal lung cells. Nature 578:224–226.

Pfeifer GP. 2020. Mechanisms of UV-induced mutations and skin cancerGenome Instab Dis 1:9–113.

Pfeifer GP, Szabó PE, Song J. 2020. Protein interactions at oxidized 5-methylcytosine bases. J Mol Biol 432(6):1718–1730.

Zeng TB, Han L, Pierce N, Pfeifer GP, Szabó PE. 2019. EHMT2 and SETDB1 protect the maternal pronucleus from 5mC oxidationProc Natl Acad Sci U S A 116:10834–10841.

Pfeifer GP, Szabó PE, Song J. 2020. Protein interactions at oxidized 5-methylcytosine basesJ Mol Biol 432(6):1718-1730.

Hahn MA, Jin SG, Li AX, Liu J, Huang Z, Wu X, Byung-Wook K, Johnson J, Bilbao ADV, Tao S, Yim JA, Fong Y, Goebbels S, Schwab MH, Lu Q, Pfeifer GP. 2019. Reprogramming of DNA methylation at NEUROD2-bound sequences during cortical neuron differentiationSci Adv 5(10):eaax0080.

Yim JH, Choi AH, Li AX, Qin H, Chang S, Tong ST, Chu P, Kim BW, Schmolze D, Lew R, Ibrahim Y, Poroyko VA, Salvatierra S, Baker A, Wang J, Wu X, Pfeifer GP, Fond Y, Hahn MA. 2019. Identification of tissue-specific DNA methylation signatures for thyroid nodule diagnosticsClin Cancer Res 25(2):544–551.

Li W, Yue F, Dai Y, Shi B, Xu G, Jiang X, Zhou X, Pfeifer GP, Liu L. 2019. Suppressor of hepatocellular carcinoma RASSF1A activates autophagy initiation and maturation. Cell Death Diff 26(8):1379–1395.

Hahn MA, Jin SG, Li AX, Liu J, Huang Z, Wu X, Kim BW, Johnson J, Bilbao ADV, Tao S, Yim JA, Fong Y, Goebbels S, Schwab MH, Lu Q, Pfeifer GP. 2019. Reprogramming of DNA methylation at NEUROD2-bound sequences during cortical neuron differentiation. Sci Adv 5(10):eaax0080.

Pfeifer GP, Szabó PE. 2018. Gene body profiles of 5-hydroxymethylcytosine: potential origin, function and use as a cancer biomarkerEpigenomics.

Pfeifer GP. 2018. Defining driver DNA methylation changes in human cancer. Intl J Mol Sci 19(4):1166.

Liu J, Wu X, Zhang H, Pfeifer GP, Lu Q. 2017. Dynamics of RNA polymerase II pausing and bivalent histone H3 methylation during neuronal differentiation in brain development. Cell Rep 20(6)1307–1318.

Hanley MP, Hahn MA, Li AX, Wu X, Lin J, Wang J, Choi A, Ouyang Z, Fong Y, Pfeifer GP, Devers TJ, Rosenberg DW. 2017. Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasiaOncogene 36(35):5035–5044.

Weng YL, An R, Cassin J, Joseph J, Mi R, Wang C, Zhong C, Jin SG, Pfeifer GP, Bellacosa A, Dong X, Hoke A, He Z, Song H, Ming GL. 2017. An intrinsic epigenetic barrier for functional axon regenerationNeuron 94(2):337–346.

Pfeifer GP. 2017. DNA methylation and mutation 2.0. Encyclopedia of Life Sciences. John Wiley & Sons, Ltd, Chichester.

Rauch TA, Pfeifer GP. 2017. Methods for assessing DNA cytosine modifications genome-wide. Handbook of Epigenetics, 2nd Edition, edited by T. Tollefsbol, Elsevier. Waltham, MA. pp. 125–134.

Pfeifer GP, Kernstine KH. 2017. DNA methylation biomarkers in lung cancer diagnosis: closer to practical use? Transl Cancer Res 6(Suppl. 1):S122–S126.

Pfeifer GP. 2016. How tobacco smoke changes the (epi)genomeScience 354(6312):549–550.

Song J, Pfeifer GP. 2016. Are there specific readers of oxidized 5-methylcytosine bases? BioEssays 38(10):1038–1047.

Iqbal K, Tran DA, Li AX, Warden C, Bai AY, Singh P, Madaj ZB, Winn ME, Wu X, Pfeifer GP, Szabó PE. 2016. High type I error and misrepresentations in search for transgenerational epigenetic inheritance: response to Guerrero-Bosagna. Genome Biol 17:154.

Pfeifer GP. 2016. Switching enhancer methylation in metastatic melanomaPigm Cell Melanoma Res 29(5):491 –493.

Pfeifer GP. 2016. Epigenetics: An elusive DNA base in mammalsNature 532:319–320.

Zhang X, Guo C, Wu X, Li AX, Liu L, Tsark W, Dammann R, Shen H, Vonderfecht SL, Pfeifer GP. 2016. Analysis of liver tumor-prone mouse models of the Hippo kinase scaffold proteins RASSF1A and SAV1Cancer Res 76:2824–2835.

Pfeifer GP. 2016. Properly dividing with YAPSci Signal 9(417):fs3.

Hainaut P, Pfeifer GP. 2016. Somatic TP53 mutations in the era of genome sequencingCold Spring Harb Perspect Med 6(11).

Jin SG, Zhang ZM, Dunwell TL, Harter MR, Wu X, Johnson J, Li Z, Liu J, Szabó PE, Lu Q, Xu GL, Song J, Pfeifer GP. 2016. Tet3 reads 5-carboxylcytosine through its CXXC domain and is a potential guardian against neurodegenerationCell Rep 14(3):493–505.

Jin SG, Xiong W, Wu X, Yang L, Pfeifer GP. 2015. The DNA methylation landscape of human melanomaGenomics 106(6):322–330. 

Jung M, Kadam S, Xiong W, Rauch TA, Jin SG, Pfeifer GP. 2015. MIRA-seq for DNA methylation analysis of CpG islandsEpigenomics 7(5):695–706.

Jung M, Pfeifer GP. 2015. Aging and DNA methylationBMC Biol 13:7.

Jung M, Jin SG, Zhang X, Xiong W, Gogoshin G, Rodin AS, Pfeifer GP. 2015. Longitudinal epigenetic and gene expression profiles analyzed by three-component analysis reveal down-regulation of genes involved in protein translation in human agingNucleic Acids Res 43(15):e100.

Iqbal K, Tran DA, Li AX, Warden C, Bai AY, Singh P, Wu X, Pfeifer GP, Szabó PE. 2015. Deleterious effects of endocrine disruptors are corrected in the mammalian germline by epigenome reprogrammingGenome Biol 16:59.

Pfeifer GP. 2015. How the environment shapes cancer genomesCurrent Opin Oncol 27(1):71–77.

Hahn MA, Li AX, Wu X, Pfeifer GP. 2015. Single base resolution analysis of 5-methylcytosine and 5-hydroxymethylcytosine by RRBS and TAB-RRBSMethods Mol Biol 1238:273–287.

Mezzanotte J, Hill V, Schmidt ML, Shinawi T, Tommasi S, Krex D, Schackert G, Pfeifer GP, Latif F, Clark GJ. 2014. RASSF6 exhibits promoter hypermethylation in metastatic melanoma and inhibits invasion in melanoma cellsEpigenetics 9(11):1496–1503.

Hahn MA, Szabó PE, Pfeifer GP. 2014. 5-hydroxymethylcytosine: a stable or transient DNA modification? Genomics 104(5):314-323.

Dunwell TL, Pfeifer GP. 2014. Drosophila genomic methylation: new evidence and new questionsEpigenomics 6(5):459–461.

Fu L, Guerrero C, Zhong N, Amato N, Liu Y, Liu S, Cai Q, Jin SG, Ji D, Niedernhofer L, Pfeifer GP, Xu GL, Wang Y. 2014. Tet-mediated formation of 5-hydroxymethylcytosine in RNAJ Am Chem Soc 136(33):11582–1585.

Hahn MA, Li AX, Wu X, Yang R, Drew DA, Rosenberg DW, Pfeifer GP. 2014. Loss of the polycomb mark from bivalent promoters leads to activation of numerous cancer-promoting genes in colorectal tumorsCancer Res 74(13):3617–3629.

Dunwell TL, McGuffin LJ, Dunwell JM, Pfeifer GP. 2013. The mysterious presence of a 5-methylcytosine oxidase in the Drosophila genome: possible explanationsCell Cycle 12(21):3357–3365.

Kalari S, Jung M, Kernstine KH, Takahashi T, Pfeifer GP. 2013. The DNA methylation landscape of small cell lung cancer suggests a differentiation defect of neuroendocrine cellsOncogene 32(30):3559–3568.

Pfeifer GP, Kadam S, Jin SG. 2013. 5-hydroxymethylcytosine and its potential roles in development and cancerEpigenetics Chromatin 6(1):10.

Hahn MA, Qiu R, Wu X, Li AX, Wang J, Zhang H, Jui J, Jin SG, Jiang Y, Pfeifer GP*, Lu Q*. 2013. Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesisCell Reports 3(2):291–300.
*Contributing authors, equal contributions

Lomniczi A, Loche A, Castellano JM, Ronnekleiv OK, Bosch M, Kaidar G, Knoll JG, Wright H, Pfeifer GP, Ojeda SR. 2013. Epigenetic control of female pubertyNat Neurosci 16(3):281–289.

Zheng L, Dai H, Zhou M, Li X, Liu C, Guo Z, Wu Z, Wu J, Wang C, Zhong J, Huang Q, Garcia-Aguilar J, Pfeifer GP, Shen B. 2012. Polyploid cells rewire DNA damage response networks to overcome replication stress-induced barriers for tumor progressionNat Commun 3:815.

Jin SG, Jiang Y, Qiu R, Rauch TA, Wang Y, Schackert G, Krex D, Lu Q, Pfeifer GP. 2011. 5-hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutationsCancer Res 71(24):7360–7365 (Priority Report).

Gu TP, Guo F, Yang H, Wu HP, Xu GF, Liu W, Xie ZG, Shi L, He X, Jin SG, Iqbal K, Shi YG, Deng Z, Szabo PE, Pfeifer GP, Li J, Xu GL. 2011. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytesNature 477(7366):606–610.

Jin SG, Wu X, Li AX, Pfeifer GP. 2011. Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res 39(12):5015–5024.

Iqbal K, Jin SG, Pfeifer GP*, Szabó PE*. 2011. Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosineProc Natl Acad Sci USA 108(9):3642–3647.
*Equally contributing authors

Guo C, Zhang X, Pfeifer GP. 2011. The tumor suppressor RASSF1A prevents dephosphorylation of the mammalian STE20-like kinases MST1 and MST2J Biol Chem 286(8):6253–6261.

Pfeifer GP, Hainaut P. 2011. Next-generation sequencing: emerging lessons on the origins of human cancerCurr Opin Oncol 23(1):62–68.

Kalari S, Pfeifer GP. 2010. Identification of driver and passenger DNA methylation in cancer by epigenomic analysisAdv Genet 70:277–308.

Jin SG, Kadam S, Pfeifer GP. 2010. Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosineNucleic Acids Res 38(11):e125.

Pfeifer GP, Dammann R, Tommasi S. 2010. RASSF proteinsCurr Biol 20(8):R344-R345.

Wu X, Rauch TA, Zhong X, Bennett WP, Latif F, Krex D, Pfeifer GP. 2010. CpG island hypermethylation in human astrocytomasCancer Res 70(7):2718–2727.

Rauch TA, Wu X, Zhong X, Riggs AD, Pfeifer GP. 2009. A human B cell methylome at 100-base pair resolutionProc Natl Acad Sci USA 106(3):671–678.

Hahn MA, Hahn T, Lee DH, Esworthy RS, Kim BW, Riggs AD, Chu FF, Pfeifer GP. 2008. Methylation of polycomb target genes in intestinal cancer is mediated by inflammationCancer Res 68(24):10280–10289.

Jin SG, Guo C, Pfeifer GP. 2008. GADD45A does not promote DNA demethylationPLoS Genet 4(3):e1000013.

Rauch TA, Zhong X, Wu X, Wang M, Kernstine KH, Wang Z, Riggs AD, Pfeifer GP. 2008. High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancerProc Natl Acad Sci USA 105(1):252–257.

Guo C, Tommasi S, Liu L, Yee JK, Dammann R, Pfeifer GP. 2007. The RASSF1A tumor suppressor protein is a component of a mammalian complex analogous to the Drosophila Hippo/Salvador/Lats tumor suppressor networkCurr Biol 17(8):700–705.

Rauch T, Wang Z, Zhang X, Zhong X, Wu X, Lau S, Kernstine K, Riggs AD, Pfeifer GP. 2007. Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assayProc Natl Acad Sci USA 104(13):5527–5532.

Rauch T, Li H, Wu X, Pfeifer GP. 2006. MIRA-assisted microarray analysis, a new technology for the determination of DNA methylation patterns, identifies frequent methylation of homeodomain-containing genes in lung cancer cellsCancer Res 66(16):7939–7947.

Liu L, Tommasi S, Lee DH, Dammann R, Pfeifer GP. 2003. Control of microtubule stability by the RASSF1A tumor suppressorOncogene 22(50):8125–8136.

Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. 2002. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancersOncogene 21(48):7435–7451.

Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP. 2000. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3Nat Genet 25(3):315–319.

Denissenko MF, Chen JX, Tang MS, Pfeifer GP. 1997. Cytosine methylation determines hotspots of DNA damage in the human P53 geneProc Natl Acad Sci USA 94(8):3893–3898.

Denissenko MF, Pao A, Tang MS, Pfeifer GP. 1996. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53Science 274(5286):430–432.

Tornaletti S, Pfeifer GP. 1994. Slow repair of pyrimidine dimers at p53 mutation hot spots in skin cancerScience 263(5152):1436–1438.

Pfeifer GP, Steigerwald SD, Mueller PR, Wold B, Riggs AD. 1989. Genomic sequencing and methylation analysis by ligation mediated PCRScience 246(4931):810–813.

Wei Cui, Ph.D.

Research Scientist

Lauren Dunkelberg, B.A.

Senior Administrative Assistant I

Zhi-jun Huang, Ph.D.

Research Scientist

Seung-Gi Jin, Ph.D.

Senior Research Scientist

Jennifer Johnson, M.S.

Research Technician

Lab Alumni

Haley Gore, M.S.

Assistant Research Technician

Pamela Himadewi, B.S.

Assistant Research Technician

Yushuai Liu

Assistant Research Technician