2. Academic Validation
  3. Domain Model Explains Propagation Dynamics and Stability of Histone H3K27 and H3K36 Methylation Landscapes

Domain Model Explains Propagation Dynamics and Stability of Histone H3K27 and H3K36 Methylation Landscapes

  • Cell Rep. 2020 Jan 28;30(4):1223-1234.e8. doi: 10.1016/j.celrep.2019.12.060.
Constance Alabert 1,  Carolin Loos 2,  Moritz Voelker-Albert 3,  Simona Graziano 4,  Ignasi Forné 3,  Nazaret Reveron-Gomez 4,  Lea Schuh 2,  Jan Hasenauer 5,  Carsten Marr 6,  Axel Imhof 7,  Anja Groth 8
Affiliations

Affiliations

  • 1 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: [email protected].
  • 2 Helmholtz Zentrum München-German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg 85764, Germany; Mathematical Modeling of Biological Systems, Center for Mathematics, Technische Universität München, Garching 85748, Germany.
  • 3 Biomedical Center, Chromatin Proteomics Group, Department of Molecular Biology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Strasse 9, 82152 Planegg-Martinsried, Germany.
  • 4 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; The Novo Nordisk Center for Protein Research (CPR), Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • 5 Helmholtz Zentrum München-German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg 85764, Germany; Mathematical Modeling of Biological Systems, Center for Mathematics, Technische Universität München, Garching 85748, Germany; Faculty of Mathematics and Natural Sciences, University of Bonn, 53115 Bonn, Germany.
  • 6 Helmholtz Zentrum München-German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg 85764, Germany. Electronic address: [email protected].
  • 7 Biomedical Center, Chromatin Proteomics Group, Department of Molecular Biology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Strasse 9, 82152 Planegg-Martinsried, Germany. Electronic address: [email protected].
  • 8 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; The Novo Nordisk Center for Protein Research (CPR), Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: [email protected].
PMID: 31995760 DOI: 10.1016/j.celrep.2019.12.060
Abstract

Chromatin states must be maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications is central in this process. However, the histone modification landscape is challenged by incorporation of new unmodified histones during each cell cycle, and the principles governing heritability remain unclear. We take a quantitative computational modeling approach to describe propagation of histone H3K27 and H3K36 methylation states. We measure combinatorial H3K27 and H3K36 methylation patterns by quantitative mass spectrometry on subsequent generations of histones. Using model comparison, we reject active global demethylation and invoke the existence of domains defined by distinct methylation endpoints. We find that H3K27me3 on pre-existing histones stimulates the rate of de novo H3K27me3 establishment, supporting a read-write mechanism in timely chromatin restoration. Finally, we provide a detailed quantitative picture of the mutual antagonism between H3K27 and H3K36 methylation and propose that it stabilizes epigenetic states across cell division.

Figures
Products