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2018 Scientific Report

  • Text
  • Institute
  • Biology
  • Methylation
  • Molecular
  • Mechanisms
  • Epigenetic
  • Michigan
  • Vari
  • Scientific

Center for Epigenetics

Center for Epigenetics STEPHEN B. BAYLIN, M.D. Dr. Baylin joined VARI as a Professor and Director's Scholar in the Center for Epigenetics in January 2015. He is co-leader of the VARI-SU2C Epigenetics Dream Team, and he devotes a portion of his time to VARI. His primary appointment is at Johns Hopkins University as the Virginia and D.K. Ludwig Professor of Oncology and Medicine and as co-head of Cancer Biology at the Sidney Kimmel Comprehensive Cancer Center. RESEARCH INTERESTS The Van Andel Research Institute–Stand Up To Cancer (VARI-SU2C) Epigenetics Dream Team is a multi-institutional effort to develop new epigenetic therapies against cancer and to move promising therapies to clinical trials. As co-leader, Dr. Baylin oversees the team’s research, which leverages the combined expertise of its members. Epigenetics is the study of how the packaging and modification of DNA influences the genes that are active or kept silent in a particular cell, and it holds untold potential for treating cancer and other diseases. Through a detailed understanding of how normal epigenetic processes work, scientists can identify erroneous epigenetic modifications that may contribute to the development and progression of cancer. Epigenetic therapies, which work by correcting these errors, have the potential to directly treat cancer and to sensitize patients to traditional treatments such as chemotherapy and promising new immunotherapy approaches. The VARI-SU2C Epigenetics Dream Team is headquartered at VARI in Grand Rapids, Michigan. It includes members from Fox Chase Cancer Center, Garvan Institute of Medical Research, Indiana University, Johns Hopkins University, Memorial Sloan Kettering Cancer Center, Rigshospitalet/University of Copenhagen, Temple University, University of Maryland, and University of Southern California. The American Association for Cancer Research, as SU2C’s scientific partner, reviews projects and provides objective scientific oversight. 22 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

PETER A. JONES, Ph.D., D.Sc. Dr. Jones received his Ph.D. from the University of London. He joined the University of Southern California in 1977 and served as Director of the USC Norris Comprehensive Cancer Center between 1993 and 2011. Dr. Jones joined VARI in 2014 as its Chief Scientific Officer and Director of the Center for Epigenetics. RESEARCH INTERESTS Our laboratory uses a holistic approach to determine how DNA methylation, nucleosome positioning, and histone modifications influence each other to bring about epigenetic changes that contribute to cancer. Some current and recent projects are summarized here. STAFF Brittany Carpenter, Ph.D. Ashley DeWitt, M.S. Minmin Liu, Ph.D. Amy Nelson Hitoshi Otani, Ph.D. Stacey Thomas, Ph.D. Rochelle Tiedemann, Ph.D. Tinghai (Peter) Xu, Ph.D. Wanding Zhou, Ph.D. Both DNA and histone modifications play important roles in suppressing endogenous retrovirus (ERV) expression in mammalian cells. ERVs, which have populated the human genome for more than 100 million years, are CpG-rich at the time of infection, but they have lost CpG content over such long time periods. We are currently examining ERVs of different ages to determine their mechanism of silencing and their ability to induce the expression of viral defense genes. The data suggest that there is an epigenetic switch in the silencing mechanism, such that older ERVs are predominately silenced by histone modification rather than DNA methylation. Following up our finding that DNA methylation inhibitors induce a state of “viral mimicry” in cancer cells, we have found that treatment of cells with a low dose of 5-azanucleoside plus vitamin C enhanced immune signals, including the increased expression of ERVs. Because many patients with hematological neoplasia are vitamin C–deficient, correction of this deficiency may improve patient response to epigenetic therapy. This work has led to an ongoing VARI-SU2C pilot clinical trial in adult patients who have MDS or AML, to assess whether vitamin C supplements can increase patient response to DNA methylation inhibitors. Another focus of the lab is the noncoding RNA nc886 (vtRNA2-1), which is variably imprinted by methylation from the mother during development and is strongly associated with the risk of both obesity and cancer. We will define the mechanism of this variable imprinting, examine the role of nc886 in normal cell physiology, and determine how chromatin structure and DNA methylation silence nc886. Taking advantage of VARI’s latest cryo-EM instrument, the Titan Krios G2, we have begun work to solve the structures of the DNA methyltransferases DNMT3A and DNMT3B bound to nucleosomes. This information will increase our understanding of how DNA methylation patterns are established and maintained by these enzymes. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 23

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