2013 Scientific Report

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Steven J. Triezenberg, Ph.D. Laboratory of Transcriptional Regulation Dr. Triezenberg received his bachelor’s degree in biology and education at Calvin College in Grand Rapids, Michigan. His Ph.D. training in cell and molecular biology at the University of Michigan was followed by postdoctoral research with Steven L. McKnight at the Carnegie Institution of Washington. Dr. Triezenberg was a faculty member of the Department of Biochemistry and Molecular Biology at Michigan State University for more than 18 years, where he also served as associate director of the Graduate Program in Cell and Molecular Biology. In 2006, Dr. Triezenberg was recruited to VAI as the founding President and Dean of the Van Andel Institute Graduate School and as a researcher in VARI. He succeeded Dr. Gordon Van Harn as the Director of the Van Andel Education Institute in January 2009. From left: Akuli, Testori, Triezenberg, Klomp, Alberts, Thellman, Pikaart Staff Amy Akuli Glen Alberts, B.S. Jennifer Klomp, M.S. Marian Testori, B.S. Students Jamie Grit Nikki Thellman, D.V.M. Visiting Scientist Michael Pikaart, Ph.D. 51
Van Andel Research Institute | <strong>Scientific</strong> <strong>Report</strong> Research Interests Our research is focused on the mechanisms that control whether genes are turned on or turned off inside cells. The genetic information encoded in DNA must first be copied, in the form of RNA, before it can be translated into the proteins that do most of the work in a cell. Some genes must be expressed more or less constantly throughout the life of any eukaryotic cell, while others must be turned on (or turned off) in particular cells either at specific times or in response to a specific signal or event. Regulation of gene expression helps determine how a given cell will function. Our laboratory explores the mechanisms that regulate the first step in that flow, the process known as transcription. We use infection by herpes simplex virus as an experimental context for exploring the mechanisms of transcriptional activation in human cells. Transcriptional activation during herpes simplex virus infection Herpes simplex virus type 1 (HSV-1) causes the common cold sore or fever blister. The initial lytic or productive infection by HSV-1 results in the obvious symptoms in the skin and mucosa, typically in or around the mouth. After the initial infection resolves, HSV-1 finds its way into nerve cells, where the virus can hide in a latent mode for long times—essentially for the lifetime of the host organism. Occasionally, some trigger event (such as emotional stress, damage to the nerve from a sunburn, or a root canal operation) will cause the latent virus to reactivate, producing new viruses in the nerve cell and sending those viruses back to the skin to cause a recurrence of the cold sore. The DNA genome of HSV-1 encodes approximately 80 different proteins. However, the virus does not have its own machinery for expressing those genes; instead, the virus must divert the gene expression machinery of the host cell. That process is triggered by a viral regulatory protein designated VP16, whose function is to stimulate transcription of the first viral genes to be expressed in the infected cell (the immediate-early, or IE, genes). Chromatin-modifying coactivators in herpes virus infections: a paradox leads to a hypothesis and yields an unexpected answer The strands of DNA in which the human genome is encoded are much longer than the diameter of a typical human cell. To help fit the DNA into the space of a cell, eukaryotic DNA is typically packaged as chromatin, in which the DNA is wrapped around “spools” of histone proteins, and these spools are then further arranged into higher-order structures. This elaborate packaging creates a problem when access is needed to the information carried in the DNA, such as when particular genes need to be expressed. This problem is solved in part by chromatin-modifying coactivator proteins, which either chemically change the histone proteins or else slide or remove them. Transcriptional activator proteins such as VP16 can recruit these chromatin-modifying coactivator proteins to target genes. We have shown this to be true for the viral genes that VP16 activates during an active infection. Curiously, however, the DNA of herpes simplex virus is not wrapped in histones inside the viral particle, and it also seems to stay relatively free of histones inside the infected cell. That observation leads to a paradox: why would VP16 recruit chromatin-modifying coactivators to the viral DNA, if the viral DNA doesn’t have much chromatin to modify? We took several approaches to test whether the coactivators recruited to viral DNA by the VP16 activation domain really play a significant role in transcriptional activation. In some experiments, we knocked down expression of given coactivators using short interfering RNAs (siRNAs). In other experiments, we used cell lines that have mutations disrupting the expression or activity of a given coactivator. We expected to find that viral gene expression was inhibited, but the experiments yielded unexpected results: in each case, expression of the viral genes was essentially unaffected. We were forced to conclude that our initial hypothesis was wrong; the coactivators, although present, are not required for viral gene expression during lytic infection. 52
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2013 Scientific Report

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