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

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 sta...

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Bibliographic Details
Published in:Genes & development 2008-08, Vol.22 (15), p.2048-2061
Main Authors: Schotta, Gunnar, Sengupta, Roopsha, Kubicek, Stefan, Malin, Stephen, Kauer, Monika, Callén, Elsa, Celeste, Arkady, Pagani, Michaela, Opravil, Susanne, De La Rosa-Velazquez, Inti A, Espejo, Alexsandra, Bedford, Mark T, Nussenzweig, André, Busslinger, Meinrad, Jenuwein, Thomas
Format: Article
Language:English
Subjects:
Alleles
Animals
Chromatin - chemistry
Chromatin - genetics
Chromatin - metabolism
Chromosome Painting
Crosses, Genetic
Gene Rearrangement
Genome
Heterozygote
Histone-Lysine N-Methyltransferase - genetics
Histone-Lysine N-Methyltransferase - metabolism
Methylation
Mice
Mice, Knockout
Protein Methyltransferases
Repressor Proteins - genetics
Repressor Proteins - metabolism
Research Paper
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.476008