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

TLDR

H4K20 methylation is a broad chromatin modification linked to diverse epigenetic functions, with distinct mono-, di-, and trimethylation states regulated by multiple enzymes. The study generated conditional null alleles of the two Suv4-20h histone methyltransferase genes in mice to analyze the roles of H4K20 methylation states. Conditional knockout of Suv4-20h genes was achieved in mice to eliminate H4K20me2 and H4K20me3, enabling assessment of the resulting chromatin changes. Suv4-20h double‑null mice die perinatally, lose nearly all H4K20me3 and H4K20me2, and exhibit a genome‑wide shift to H4K20me1 that increases sensitivity to DNA damage, impairs double‑strand break repair, causes chromosomal aberrations, disrupts immunoglobulin class‑switch recombination, and depletes lymphoid progenitor stem cells, demonstrating that H4K20me1 conversion compromises genome integrity and DNA‑rearranging differentiation.

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.