title: A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse.
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.
authors.affiliation: Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, A-1030 Vienna, Austria. Gunnar.Schotta@med.uni-muenchen.de
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schotta
authors.forename: Roopsha
authors.initials: R
authors.lastname: Sengupta
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicek
authors.forename: Stephen
authors.initials: S
authors.lastname: Malin
authors.forename: Monika
authors.initials: M
authors.lastname: Kauer
authors.forename: Elsa
authors.initials: E
authors.lastname: Callén
authors.forename: Arkady
authors.initials: A
authors.lastname: Celeste
authors.forename: Michaela
authors.initials: M
authors.lastname: Pagani
authors.forename: Susanne
authors.initials: S
authors.lastname: Opravil
authors.forename: Inti A
authors.initials: IA
authors.lastname: De La Rosa-Velazquez
authors.forename: Alexsandra
authors.initials: A
authors.lastname: Espejo
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bedford
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Jenuwein
mesh_terms: 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
chemical_list: D002843:Chromatin; D012097:Repressor Proteins; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase