11 months ago

2018 Scientific Report

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

Center for Epigenetics

Center for Epigenetics PIROSKA E. SZABÓ, Ph.D. Dr. Szabó earned an M.Sc. in biology and a Ph.D. in molecular biology from József Attila University, Szeged, Hungary. She joined VARI in 2014 as an Associate Professor. RESEARCH INTERESTS Our laboratory studies the molecular mechanisms responsible for resetting the mammalian epigenome between generations, globally and specifically in the context of genomic imprinting. We focus on how DNA methylation patterns are established in germ cells and how some of those are protected in the zygote and in the embryo. STAFF Brianna Bixler, B.S. Ji Liao, Ph.D. Amy Nelson Tie-Bo Zeng, Ph.D. STUDENTS Brianna Busscher Yingying Meng, M.S. The role of broad transcription and dynamic chromatin changes in the germline Correctly setting up male or female gamete-specific methylation patterns is vitally important for fertility, development, and health. Our genome-wide mapping results have revealed that DNA methylation in fetal male germ cells (prospermatogonia) occurs by default along a profile of broad, low-level transcription. We have also found that dynamically increasing or diminishing H3K4 methylation at specific sequences is predictive of escaping or attaining DNA methylation, respectively, in the male germline. We hypothesize that transcription run-through is required for establishing default, broad DNA methylation in the prospermatogonia genome, including paternal imprinted differentially methylated regions (DMRs). Dynamic changes in H3K4me by H3K4 demethylases (KDMs) and H3K4 methyltransferases (HMTs), on the other hand, provide a pattern for de novo DNA methylation. We are addressing these questions using experimental approaches of mouse genetics and epigenomics. Maternal effects of histone methyltransferases Crucial events in the early embryo, such as reaching totipotency and embryonic genome activation, depend on accurate levels of epigenetic modifiers deposited in the egg. We are only beginning to understand the underlying epigenetic mechanisms in these events. We and others have shown that genome-wide DNA demethylation in the zygote involves sequential TET-mediated oxidation of 5mC to 5hmC, 5fC, and 5caC in the paternal pronucleus. Specific loci and the entire maternal pronucleus, however, are protected from TET-initiated DNA demethylation; this protection involves histone H3K9 methylation. Using mouse genetics and epigenomics, we will genetically identify the mechanistic connections between maternally deposited HMTs, DNA methylation, and the developmental potential of the embryo. 30 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

TIMOTHY J. TRICHE, JR., Ph.D. Dr. Triche earned his Ph.D. from the University of Southern California in 2013. He joined VARI in the autumn of 2017 as an Assistant Professor in the Center for Epigenetics. RESEARCH INTERESTS Our laboratory develops statistical and mathematical methods to dissect pediatric and adult diseases, with a focus on cancers of the blood in children. We study interactions between genetic factors and environmental factors (deficiencies and exposures), particularly where epigenetic mediation plays a major role, such as in immune response and evasion. STAFF Amy Nelson VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 31

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