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  3. DNA sequence and chromatin modifiers cooperate to confer epigenetic bistability at imprinting control regions

DNA sequence and chromatin modifiers cooperate to confer epigenetic bistability at imprinting control regions

  • Nat Genet. 2022 Nov;54(11):1702-1710. doi: 10.1038/s41588-022-01210-z.
Stefan Butz 1 2,  Nina Schmolka 1 3,  Ino D Karemaker 1,  Rodrigo Villaseñor 1 4,  Isabel Schwarz 1,  Silvia Domcke 5 6 7,  Esther C H Uijttewaal 8,  Julian Jude 9,  Florian Lienert 5 6,  Arnaud R Krebs 5 10,  Nathalie P de Wagenaar 11,  Xue Bao 11,  Johannes Zuber 9 12,  Ulrich Elling 8,  Dirk Schübeler 5 6,  Tuncay Baubec 13 14
Affiliations

Affiliations

  • 1 Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
  • 2 Molecular Life Science PhD Program of the Life Science Zurich Graduate School, University of Zurich and ETH Zurich, Zurich, Switzerland.
  • 3 Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
  • 4 Division of Molecular Biology, Biomedical Center Munich, Ludwig-Maximilians-University, Munich, Germany.
  • 5 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • 6 Faculty of Science, University of Basel, Basel, Switzerland.
  • 7 Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • 8 Institute of Molecular Biotechnology Austria (IMBA), Vienna BioCenter (VBC), Vienna, Austria.
  • 9 Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria.
  • 10 European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
  • 11 Division of Genome Biology and Epigenetics, Institute of Biodynamics and Biocomplexity, Department of Biology, Science Faculty, Utrecht University, Utrecht, the Netherlands.
  • 12 Medical University of Vienna, Vienna BioCenter (VBC), Vienna, Austria.
  • 13 Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland. t.baubec@uu.nl.
  • 14 Division of Genome Biology and Epigenetics, Institute of Biodynamics and Biocomplexity, Department of Biology, Science Faculty, Utrecht University, Utrecht, the Netherlands. t.baubec@uu.nl.
PMID: 36333500 DOI: 10.1038/s41588-022-01210-z
Abstract

Genomic imprinting is regulated by parental-specific DNA methylation of imprinting control regions (ICRs). Despite an identical DNA sequence, ICRs can exist in two distinct epigenetic states that are memorized throughout unlimited cell divisions and reset during germline formation. Here, we systematically study the genetic and epigenetic determinants of this epigenetic bistability. By iterative integration of ICRs and related DNA sequences to an ectopic location in the mouse genome, we first identify the DNA sequence features required for maintenance of epigenetic states in embryonic stem cells. The autonomous regulatory properties of ICRs further enabled us to create DNA-methylation-sensitive reporters and to screen for key components involved in regulating their epigenetic memory. Besides DNMT1, UHRF1 and ZFP57, we identify factors that prevent switching from methylated to unmethylated states and show that two of these candidates, ATF7IP and ZMYM2, are important for the stability of DNA and H3K9 methylation at ICRs in embryonic stem cells.

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