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2016 Scientific Report

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GERD PFEIFER, PH.D. Dr. Pfeifer earned his M.S. in pharmacology in 1981 and his Ph.D. in biochemistry in 1984 from Goethe University in Frankfurt, Germany. He most recently held the Lester M. and Irene C. Finkelstein Chair in Biology at the City of Hope in Duarte, California, before joining VARI in 2014 as a Professor. STAFF ZHIJUN HUANG, PH.D. SEUNG-GI JIN, PH.D. JENNIFER JOHNSON, M.S. JIYOUNG YU, PH.D. RESEARCH OVERVIEW The laboratory studies epigenetic mechanisms of disease, with a focus on DNA methylation and the role of 5-hydroxymethylcytosine in cancer and other diseases. Specifically, the lab studies hypermethylation in cancer genes with the intent of determining the mechanisms and significance of CpG island methylation. The work centers on the hypothesis that CpG island hypermethylation in tumors is driven by one or a combination of the following: carcinogenic agents, inflammation, imbalances in methylation and demethylation pathways, oncogene activation leading to epigenetic changes, and dysfunction of the Polycomb repression complex. The removal of methyl groups from DNA has recently been recognized as an important pathway in cancer and possibly in other diseases. Our lab studies mechanisms of 5-methylcytosine oxidation. DNA methylation in cancer To effectively study genome-wide DNA methylation patterns, we previously developed the methylated CpG island recovery assay (MIRA), which is used in combination with sequencing to identify commonly methylated genes in human cancers and normal tissues. We investigate mechanisms of cancer-associated DNA hypermethylation using DNA-methylation and chromatin-component mapping in normal and malignant cells, as well as bioinformatics approaches and functional studies. 38 Van Andel Research Institute | Scientific Report

Tet3 and related proteins We have identified three different isoforms of the Tet3 5-methylcytosine oxidase and characterized them using biochemical, functional, and genetic approaches. We observed that one isoform of Tet3 specifically binds to 5-carboxylcytosine, thus establishing an anchoring mechanism of Tet3 to its reaction product, which may aid in localized 5-methylcytosine oxidation and removal. We also study several Tet-associated proteins, trying to understand their biological roles. 5-methylcytosine oxidation and neurodegeneration Using ChIP sequencing, we mapped one of the isoforms of Tet3 in neuronal cell populations. Tet3 has a rather limited genomic distribution and is targeted to the transcription start sites of defined sets of genes, many of which function within the lysosome and autophagy pathways. We know these pathways are defective in neurodegenerative diseases. We are exploring the mechanistic consequences of 5-methylcytosine oxidation in this disease group, with the long-term goal of determining whether neurodegeneration has an epigenetic origin. RECENT PUBLICATIONS Jin, Seung-Gi, Zhi-Min Zhang, Thomas L. Dunwell, Matthew R. Harter, Xiwei Wu, Jennifer Johnson, Zheng Li, Jiancheng Liu, Piroska E. Szabó, et al. 2016. Tet3 reads 5-carboxylcytosine through its CXXC domain and is a potential guardian against neurodegeneration. Cell Reports 14(3): 493–505. Jung, Marc, Seung-Gi Jin, Xiaoying Zhang, Wenying Xiong, Grigoriy Gogoshin, Andrei S. Rodin, and Gerd P. Pfeifer. 2015. Longitudinal epigentic and gene expression profiles analyzed by three-component analysis reveal down-regulation of genes involved in protein translation in human aging. Nucleic Acids Research 43(15): e100. Jung, Marc, Swati Kadam, Wenying Xiong, Tibor A. Rauch, Seung-Gi Jin, and Gerd P. Pfeifer. 2015. MIRA-seq for DNA methylation analysis of CpG islands. Epigenomics 7(5): 695–706. CENTER FOR EPIGENETICS 39

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