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2018 Scientific Report

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  • Institute
  • Biology
  • Methylation
  • Molecular
  • Mechanisms
  • Epigenetic
  • Michigan
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Center for Epigenetics

Center for Epigenetics STEVEN J. TRIEZENBERG, Ph.D. Dr. Triezenberg earned his Ph.D. at the University of Michigan. He was a faculty member at Michigan State University for more than 18 years before joining VARI in 2006 as the founding Dean of Van Andel Institute Graduate School and as a VARI Professor. RESEARCH INTERESTS Our research explores the mechanisms that control how genes are expressed inside cells, with a special interest in the processes that activate transcription of genetic information from DNA into RNA. We study those mechanisms in the context of infection by herpes simplex virus type 1 (HSV-1), the cause of cold sores. STAFF Glen Alberts, B.S. Susanne Miller-Schachinger, B.B.A. . STUDENT Nikki Thellman, D.V.M. (Ph.D., May 2017) Some of our work looks at early stages of lytic or productive infection by HSV-1, which results in the obvious (and painful) cold-sore symptoms near the mouth. We have explored how a particular viral protein, VP16, activates the first viral genes that are expressed during lytic infection. We are now looking at proteins of the host cell that affect the early stages of infection, some of which control how the virus gets into a cell and some that control how the VP16 protein performs its functions. This approach may yield new ideas for antiviral drugs that can block HSV infections. After the initial infection resolves, HSV-1 finds its way into nerve cells, where the virus can remain in a latent mode for the entire life of the host. Occasionally, some stressful event will cause the latent virus to reactivate, producing new viruses in the nerve cell and sending them back to the skin to cause a recurrence of the cold sore. We are investigating the role that VP16 might play during this reactivation. We are especially interested in the epigenetic regulators that might be involved in unpacking the chromatin that silences the latent viral DNA. Our present hypothesis is that epigenetic coactivators recruited by VP16 are required to open up chromatin as an early step in reactivating the viral genes from latency. We are currently testing this hypothesis in quiescent infections of cultured human nerve cells. 32 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

RECENT CENTER PUBLICATIONS Azad, Nilofer S., Anthony el-Khoueiry, Jun Yin, Ann L. Oberg, Patrick Flynn, Douglas Adkins, Anup Sharma, Daniel J. Weisenberger, Thomas Brown, Prakriti Medvari, Peter A. Jones, Hariharan Easwaran, Ihab Kamel, Nathan Bahary, George Kim, Joel Picus, Henry C. Pitot, Charles Erilichman, Ross Donehower, Hui Shen, Peter W. Laird, Richard Piekarz, Stephen Baylin, and Nita Ahuja. 2017. Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/Stand Up 2 Cancer study. Oncotarget 8(21): 35326–35338. Cancer Genome Atlas Research Network, The. 2017. Integrated genomic characterization of oesophageal carcinoma. Nature 541(7636): 169–175. Cherniack, Andrew D., Hui Shen, Vonn Walter, Chip Stewart, Bradley A. Murray, Reanne Bowlby, Xin Hu, Shiyun Ling, Robert A. Soslow, Russell R. Broaddus, Rosemary E. Zuna, Gordon Robertson, Peter W. Laird, Raju Kucherlapati, Gordon B. Mills, The Cancer Genome Atlas Research Network, John N. Weinstein, Jiashan Zhang, Rehan Akbani, and Douglas A. Levine. 2017. Integrated molecular characterization of uterine carcinosarcoma. Cancer Cell 31(3): 411–423. Connolly, Roisin M., Huili Li, Rachel C. Jankowitz, Zhe Zhang, Michelle A. Rudek, Stacie C. Jeeter, Shannon A. Slater, Penny Powers, Antonio C. Wolff, John H. Fetting, Adam Burufsky, Richard Piekarz, Nita Ahuja, Peter W. Laird, Hui Shen, Daniel J. Weisenberger, Leslie Cope, James G. Herman, George Somlo, Garcia Agustin A., Peter A. Jones, Stephen B. Baylin, Nancy E. Davidson, Cynthia A. Zahnow, and Vered Stearns. 2017. Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat: a Phase II National Cancer Institute/Stand Up to Cancer study. Clinical Cancer Research 23(11): 2691–2701. Cornett, Evan M., Bradley M. Dickson, and Scott B. Rothbart. 2017. Analysis of histone antibody specificity with peptide microarrays. Journal of Visualized Experiments 126: e55912. Georgescu, Roxana, Zuanning Yuan, Lin Bai, Ruda de Luna Almeida Santos, Jingchuan Sun, Dan Zhang, Olga Yurieva, Huilin Li, and Michael E. O’Donnell. 2017. Structure of eukaryotic CMG helicase at a replication fork and implications to replisome architecture and origin initiation. Proceedings of the National Academy of Sciences U.S.A. 114(5): D697–E706. Hanley, M.P., M.A. Hahn, A.X. Li, X. Wu, J. Lin, A.H. Choi, Z. Ouyang, Y. Fong, G.P. Pfeifer, T.J. Devers, and D.W. Rosenberg. 2017. Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia. Oncogene 36(35): 5035–5044. Helbo, Alexandra Søgaard, Fides D. Lay, Peter A. Jones, Gangning Liang, and Kirsten Grønbaek. 2017. Nucleosome positioning and NDR structure at RNA polymerase III promoters. Scientific Reports 7: 41947 Lakshminarasimhan, Ranjani, Claudia Andreu-Vieyra, Kate Lawrenson, Christopher E. Duymich, Simon A. Gayther, Gangning Liang, and Peter A. Jones. 2017. Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with epigenetic reprogramming in non-tumorigenic endometriotic cells. Cancer Letters 401: 11–19. Lee, Kwang-Ho, Shirley Oghamian, Jin-A Park, Liang Kang, and Peter W. Laird. 2017. The REMOTE-control system: a system for reversible and tunable control of endogenous gene expression in mice. Nucleic Acids Research 45(21): 12256–12269. Ma, Honglei, Jingbo Duan, Jiyuan Ke, Yuanzheng He, Xin Gu, Ting-Hai Xu, Hong Yu, Yonghong Wang, Joseph S. Brunzelle, Yi Jiang, Scott B. Rothbart, H. Eric Xu, Jiayang Li, and Karsten Melcher. 2017. A D53 repression motif induces oligomerization of TOPLESS corepressors and promotes assembly of a corepressor-nucleosome complex. Science Advances 3(6): e1601217. Noguchi, Yasunori, Auanning Yuan, Lin Bai, Sarah Schneider, Gongpu Zhao, Bruce Stillman, Christian Speck, and Huilin Li. 2017. Cryo-EM structure of Mcm2-7 double hexamer on DNA suggests a lagging-strand DNA extrusion model. Proceedings of the National Academy of Sciences U.S.A. 114(45): E9529–E9538. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 33

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