A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse
2008; Cold Spring Harbor Laboratory Press; Volume: 22; Issue: 15 Linguagem: Inglês
10.1101/gad.476008
ISSN1549-5477
AutoresGunnar Schotta, Roopsha Sengupta, Stefan Kubicek, Stephen Malin, Monika Kauer, Elsa Callén, Arkady Celeste, Michaela Pagani, Susanne Opravil, Inti A. De La Rosa-Velázquez, Alexsandra Espejo, Mark T. Bedford, André Nussenzweig, Meinrad Busslinger, Thomas Jenuwein,
Tópico(s)Genomics and Chromatin Dynamics
ResumoH4K20 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.
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