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.[Keywords: H4K20 methylation; Suv4-20h enzymes; DNA repair; genome integrity; B-cell differentiation; class-switch recombination] Supplemental material is available at http://www.genesdev.org. Received February 18, 2008; revised version accepted May 30, 2008. Histone lysine methylation is a central epigenetic modification in eukaryotic chromatin. Five major positions for lysine methylation exist in the histone N termini, each with distinct regulatory functions. The repressive methyl marks H3K9, H3K27, and H4K20 are involved in constitutive heterochromatin formation and gene repression, X inactivation, and Polycomb silencing, and in DNA damage repair, mitotic chromosome condensation, and gene regulation (Allis et al. 2007). Additional complexity arises through the fact that histone methylation can be present in three distinct states (mono, di, or tri), which may have different biological readouts depending on the association with specific binding partners. Although there has been significant insight in histone lysine methylation pathways, we still know very little about how the diverse methylation states affect chromatin biology.H4K20 methylation is evolutionarily conserved from Schizosaccharomyces pombe to man . In mammalian cells, H4K20me1 is exclusively induced by the PrSet7/KMT5A histone methyltransferase (HMTase) (Fang et al. 2002;Nishioka et al. 2002), where it has been linked with transcriptional repression (Karachentsev et al. 2005) and X inactivation (Kohlmaier et al. 2004). More recently, genome-wide profiling of H4K20me1 also revealed enrichment of this mark across actively transcribed genes (Papp and Muller 2006;Vakoc et al. 2006). H4K20me1 is very dynamic throughout the cell cycle and becomes highly enriched during S phase (Jorgensen et al. 2007;Tardat et al. 2007;Huen et al. 2008

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

“…Although the recruitment of 53BP1 to DNA damage sites is only partially impaired in the absence of SIRT7, this is not unusual in other models in which chromatin remodeling at DSB is compromised. Some examples include the Suv4‐20h histone methyltransferase double‐null mice, in which H4K20me2 is reduced (Schotta et al , 2008); the SIRT2 KO mice by its impact on the H4K20me1 methyl transferase PRSET7 (Serrano et al , 2013). …”

Histone H4 Lysine 20 (H4K20) Methylation, Expanding the Signaling Potential of the Proteome One Methyl Moiety at a Time

“…Depending on the cell type, up to ϳ80% of H4 molecules can be dimethylated, whereas H4K20me1 and H4K20me3 are generally less abundant, for example being present on 10 and 5% of nucleosomes in asynchronous HeLa cells, respectively, with similar ratios observed in mouse embryonic fibroblasts (MEFs) and other cell types (13)(14)(15)(16). Three distinct SET domains containing lysine (K) methyltransferase (KMT) enzymes, SETD8 (SET8, PR-SET7), SUV4-20H1, and SUV4-20H2, are responsible for the generation of the three different methyl states of H4K20 (17)(18)(19)(20).…”

L3MBTL1 polycomb protein, a candidate tumor suppressor in del(20q12) myeloid disorders, is essential for genome stability

“…SUV4-20 methyltransferase catalyzes the di-and trimethylation of H4K20, and Suv4-20 knockout mice, which can only form the H4K20me1 derivative, are more sensitive to DNA damage than wild-type mice (23). Loss of PrSet7, a histone methyltransferase that monomethylates lysine 20 on histone H4, induces DNA damage in human, mouse, and Drosophila cells.…”