A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse

  1. Gunnar Schotta1,4,5,7,
  2. Roopsha Sengupta1,4,
  3. Stefan Kubicek1,
  4. Stephen Malin1,
  5. Monika Kauer1,
  6. Elsa Callén2,
  7. Arkady Celeste2,
  8. Michaela Pagani1,
  9. Susanne Opravil1,
  10. Inti A. De La Rosa-Velazquez1,
  11. Alexsandra Espejo3,
  12. Mark T. Bedford3,
  13. André Nussenzweig2,
  14. Meinrad Busslinger1, and
  15. Thomas Jenuwein1,6
  1. 1 Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, A-1030 Vienna, Austria;
  2. 2 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
  3. 3 University of Texas, M.D. Anderson Cancer Center, Science Park Research Division, Smithville, Texas 79857, USA
  1. 4 These authors contributed equally to this work.

Abstract

H4K20 methylation is a broad chromatin modification that has been linked with diverse epigenetic functions. Several enzymes target H4K20 methylation, consistent with distinct mono-, di-, and trimethylation states controlling different biological outputs. To analyze the roles of H4K20 methylation states, we generated conditional null alleles for the two Suv4-20h histone methyltransferase (HMTase) genes in the mouse. Suv4-20h-double-null (dn) mice are perinatally lethal and have lost nearly all H4K20me3 and H4K20me2 states. The genome-wide transition to an H4K20me1 state results in increased sensitivity to damaging stress, since Suv4-20h-dn chromatin is less efficient for DNA double-strand break (DSB) repair and prone to chromosomal aberrations. Notably, Suv4-20h-dn B cells are defective in immunoglobulin class-switch recombination, and Suv4-20h-dn deficiency impairs the stem cell pool of lymphoid progenitors. Thus, conversion to an H4K20me1 state results in compromised chromatin that is insufficient to protect genome integrity and to process a DNA-rearranging differentiation program in the mouse.

Keywords

Footnotes

  • 5 Present address: Munich Center for Integrated Protein Science (CiPSM) and Adolf-Butenandt-Institute, Ludwig-Maximilians-Universität München, Schillerstrasse 44, 80336 Munich, Germany.

  • 6 Corresponding authors.

    6 E-MAIL jenuwein{at}imp.univie.ac.at; FAX 43-1-798-7153.

  • 7 E-MAIL Gunnar.Schotta{at}med.uni-muenchen.de; FAX 49-89-218075425.

  • Supplemental material is available at http://www.genesdev.org.

  • Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.476008.

    • Received February 18, 2008.
    • Accepted May 30, 2008.
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