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2016 Scientific Report

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SCOTT ROTHBART, PH.D. Dr. Rothbart earned a Ph.D. in pharmacology and toxicology from Virginia Commonwealth University in 2010. He joined VARI in April 2015 as an Assistant Professor. STAFF EVAN CORNETT, PH.D. BRADLEY DICKSON, PH.D. ROCHELLE TIEDEMANN, PH.D. STUDENT ROBERT VAUGHAN, B.S. RESEARCH INTERESTS Two major epigenetic marks regulating the structure and function of eukaryotic chromatin are the methylation of DNA and post-translational modifications (PTMs) of histone proteins. Breakthroughs in our understanding of chromatin function have been made through the identification of protein machineries that incorporate (write), remove (erase), and bind (read) these epigenetic marks. Chromatin modification and remodeling shape cellular identity, and it is becoming increasingly apparent that deregulation of epigenetic signaling contributes to, and may cause, the initiation and progression of cancer and other human diseases. Unlike genetic abnormalities, chromatin modifications are reversible, making the writers, erasers, and readers of these marks attractive therapeutic targets. The goal of our research is to define the molecular details of chromatin accessibility, interaction, and function. We are particularly interested in understanding how DNA and histone modifications work together as a language or code that is read and interpreted by specialized proteins to orchestrate the dynamic functions of chromatin. We hope our studies will lead to a better understanding of the etiology of disease and will contribute to the discovery of effective therapeutic approaches that target the epigenetic machinery. Mechanics of chromatin interaction It appears that many chromatin-associated factors have multiple known (or predicted) chromatin regulatory domains, both within a single protein and within the subunits of complexes. There is a diverse and exciting potential here, a previously underappreciated layer of complexity and specificity to chromatin recognition and regulation. Our studies are using expertise in biochemistry, computational and molecular biophysics, and cell biology to define the molecular underpinnings of multivalency and allostery in chromatin interaction and function. 40 Van Andel Research Institute | Scientific Report

Mechanisms regulating the inheritance of DNA methylation Application of microarray technology to the study of histone PTMs. The faithful inheritance of DNA methylation patterns is essential for normal mammalian development and long-term transcriptional silencing. We recently discovered that the E3 ubiquitin ligase UHRF1 is a key regulator of this process through its interaction with a histone signature of transcriptionally silent heterochromatin. Current studies are focused on defining the molecular interconnections between UHRF1, DNMTs, and chromatin, and on elucidating the role of UHRF1 deregulation in tumor initiation and progression. We recently developed a histone peptide microarray platform that has greatly improved our understanding of histone PTM function in development and disease, as well as during the fundamental processes of transcription, chromatin organization, and DNA repair. We are developing several new microarray-based platforms to enable high-throughput discovery of histone PTM function. Two areas of focus are to expand the utility of our current histone peptide array in defining the influence of the “histone code” on writers and erasers of these marks and to develop a multiplex array assay for comparative profiling of histone PTM patterns in stages of differentiation and disease. RECENT PUBLICATIONS Rothbart, Scott B., Bradley M. Dickson, Jesse R. Raab, Adrian T. Grzybowski, Krzysztof Krajewski, Angela H. Guo, Erin K. Shanle, Steven Z. Josefowicz, Stephen M. Fuchs, et al. 2015. An interactive database for the assessment of histone antibody specificity. Molecular Cell 59(3): 502–511. Simon, Jeremy M., Joel S. Parker, Feng Liu, Scott B. Rothbart, Slimane Ait-Si-Ali, Brian D. Strahl, Jian Jin, Ian J. Davis, Amber L. Moseley, and Samantha G. Pattenden. 2015. A role for widely interspaced zinc finger (WIZ) in retention of the G9a methyltransferase on chromatin. Journal of Biological Chemistry 290(43): 26088–26102. Zhang, Zhi-Min, Scott B. Rothbart, David F. Allison, Qian Cai, Joseph S. Harrison, Lin Li, Yinsheng Wang, Brian D. Strahl, Gang Greg Wang, and Jikui Song. 2015. An allosteric interaction links USP7 to deubiquitination and chromatin targeting of UHRF1. Cell Reports 12(9): 1400–1406. CENTER FOR EPIGENETICS 41

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