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Impairment of Dna Methylation Maintenance Is the Main Cause of Global Demethylation in Naive Embryonic Stem Cells Publisher Pubmed



Von Meyenn F1 ; Iurlaro M1 ; Habibi E2 ; Liu NQ2 ; Salehzadehyazdi A3, 10 ; Santos F1 ; Petrini E1 ; Milagre I1 ; Yu M4, 5 ; Xie Z6 ; Kroeze LI7 ; Nesterova TB8 ; Jansen JH7 ; Xie H6 Show All Authors
Authors
  1. Von Meyenn F1
  2. Iurlaro M1
  3. Habibi E2
  4. Liu NQ2
  5. Salehzadehyazdi A3, 10
  6. Santos F1
  7. Petrini E1
  8. Milagre I1
  9. Yu M4, 5
  10. Xie Z6
  11. Kroeze LI7
  12. Nesterova TB8
  13. Jansen JH7
  14. Xie H6
  15. He C4, 5
  16. Reik W1, 9
  17. Stunnenberg HG2
Show Affiliations
Authors Affiliations
  1. 1. Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, United Kingdom
  2. 2. Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, 6525GA, Netherlands
  3. 3. Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, 929 East 57th Street, Chicago, 60637, IL, United States
  5. 5. Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, 60637, IL, United States
  6. 6. Virginia Bioinformatics Institute and Department of Biological Sciences, Virginia Tech, Blacksburg, 24060, VA, United States
  7. 7. Department of Laboratory Medicine, Laboratory of Hematology, Radboud Univ. Nijmegen Medical Centre and Radboudumc Inst. for Molecular Life Sciences (RIMLS), Nijmegen, 6525GA, Netherlands
  8. 8. Developmental Epigenetics Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom
  9. 9. Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom
  10. 10. Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, 18051, Germany

Source: Molecular Cell Published:2016


Abstract

Global demethylation is part of a conserved program of epigenetic reprogramming to naive pluripotency. The transition from primed hypermethylated embryonic stem cells (ESCs) to naive hypomethylated ones (serum-to-2i) is a valuable model system for epigenetic reprogramming. We present a mathematical model, which accurately predicts global DNA demethylation kinetics. Experimentally, we show that the main drivers of global demethylation are neither active mechanisms (Aicda, Tdg, and Tet1-3) nor the reduction of de novo methylation. UHRF1 protein, the essential targeting factor for DNMT1, is reduced upon transition to 2i, and so is recruitment of the maintenance methylation machinery to replication foci. Concurrently, there is global loss of H3K9me2, which is needed for chromatin binding of UHRF1. These mechanisms synergistically enforce global DNA hypomethylation in a replication-coupled fashion. Our observations establish the molecular mechanism for global demethylation in naive ESCs, which has key parallels with those operating in primordial germ cells and early embryos. © 2016.
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