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 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.
Schotta
Gunnar
G
Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, A-1030 Vienna, Austria. Gunnar.Schotta@med.uni-muenchen.de
Sengupta
Roopsha
R
Kubicek
Stefan
S
Malin
Stephen
S
Kauer
Monika
M
Callén
Elsa
E
Celeste
Arkady
A
Pagani
Michaela
M
Opravil
Susanne
S
De La Rosa-Velazquez
Inti A
IA
Espejo
Alexsandra
A
Bedford
Mark T
MT
Nussenzweig
André
A
Busslinger
Meinrad
M
Jenuwein
Thomas
T
D000483:Alleles; D000818:Animals; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020223:Chromosome Painting; D003433:Crosses, Genetic; D015321:Gene Rearrangement; D016678:Genome; D006579:Heterozygote; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D011496:Protein Methyltransferases; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D012097:Repressor Proteins; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase