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2016 Scientific Report

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Mapping of the mammalian

Mapping of the mammalian 5-methylcytosine oxidase Tet3. Top left: Ribbon representation of the mTet3 CXXC domain (light blue) bound to CcaCG DNA (tan). The zinc ions in the CXXC domain and the carboxylates in DNA are shown as green and red spheres, respectively. Top right: Electrostatic surface representation, with positive charge shown as blue and negative charge as red. Bottom: ChiP-seq data shows that Tet3FL peaks center on transcription start sites (horizontal arrows) for four lysosome-related genes. The peaks from neuronal progenitors (NPC) and mouse brain cells correspond to the locations of low 5-methylcytosine content in the DNA sequence of NPCs and mouse embryonic stem cells (Stadler et al., 2011). Figure from the Pfeifer laboratory. 42 Van Andel Research Institute | Scientific Report

HUI SHEN, PH.D. Dr. Shen earned her Ph.D. at the University of Southern California in genetic, molecular, and cellular biology. She joined VARI in September 2014 as an Assistant Professor. STAFF HUIHUI FAN, PH.D. WANDING ZHOU, PH.D. RESEARCH INTERESTS The laboratory focuses on the epigenome and its interaction with the genome in various diseases, with a specific emphasis on female cancers and cross-cancer comparisons. We use bioinformatics as a tool to understand the etiology, cell of origin, and epigenetic mechanisms of various diseases and to devise better approaches for cancer prevention, detection, therapy, and monitoring. We have extensive experience with genome-scale DNA methylation profiles in primary human samples, and we have made major contributions to epigenetic analysis within The Cancer Genome Atlas (TCGA). DNA methylation is ideally suited for deconstructing heterogeneity among cell types within a tissue sample. In cancer research, this approach can be used for cancercell clonal evolution studies or for quantifying normal cell infiltration and stromal composition. The latter can provide insights into the tumor microenvironment, and in noncancer studies it can be a useful tool for accurately estimating cell populations and providing insights into lineage structures and population shifts in disease. In addition, we are interested in translational applications of epigenomic technology. To this end, we bring markers emerging from our bioinformatics analysis into clinical assay development, marker panel assembly, and optimization, with the ultimate goal of clinical testing and validation. RECENT PUBLICATIONS Cancer Genome Atlas Research Network. 2016. Comprehensive molecular characterization of papillary renal-cell carcinoma. New England Journal of Medicine 374(2): 135–145. Ciriello, Giovanni, Michael L. Gatza, Andrew H. Beck, Matthew D. Wilkerson, Suhn K Rhie, Alessandro Pastore, Hailei Zhang, Michael McLellan, Christina Yau, et al. 2015. Comprehensive molecular portraits of invasive lobular breast cancer. Cell 163(2): 506–519. Yao, Lijing, Hui Shen, Peter W. Laird, Peggy J. Farnham, and Benjamin P. Berman. 2015. Inferring regulatory element landscapes and transcription factor networks from cancer methylomes. Genome Biology 16: 105. CENTER FOR EPIGENETICS 43

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