A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse
- Gunnar Schotta1,4,5,7,
- Roopsha Sengupta1,4,
- Stefan Kubicek1,
- Stephen Malin1,
- Monika Kauer1,
- Elsa Callén2,
- Arkady Celeste2,
- Michaela Pagani1,
- Susanne Opravil1,
- Inti A. De La Rosa-Velazquez1,
- Alexsandra Espejo3,
- Mark T. Bedford3,
- André Nussenzweig2,
- Meinrad Busslinger1, and
- Thomas Jenuwein1,6
- 1 Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, A-1030 Vienna, Austria;
- 2 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
- 3 University of Texas, M.D. Anderson Cancer Center, Science Park Research Division, Smithville, Texas 79857, USA
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↵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
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↵5 Present address: Munich Center for Integrated Protein Science (CiPSM) and Adolf-Butenandt-Institute, Ludwig-Maximilians-Universität München, Schillerstrasse 44, 80336 Munich, Germany.
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↵6 Corresponding authors.
↵6 E-MAIL jenuwein{at}imp.univie.ac.at; FAX 43-1-798-7153.
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↵7 E-MAIL Gunnar.Schotta{at}med.uni-muenchen.de; FAX 49-89-218075425.
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Supplemental material is available at http://www.genesdev.org.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.476008.
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- Received February 18, 2008.
- Accepted May 30, 2008.
- Copyright © 2008, Cold Spring Harbor Laboratory Press