A Chromatin-wide Transition to H4K20 Monomethylation Impairs Genome Integrity and Programmed DNA Rearrangements in the Mouse

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2008 Aug 5

PMID 18676810

Citations 245

Authors

Gunnar Schotta

Roopsha Sengupta

Stefan Kubicek

Stephen Malin

Monika Kauer

Elsa Callen

Arkady Celeste

Michaela Pagani

Susanne Opravil

Inti A de la Rosa-Velazquez

Alexsandra Espejo

Mark T Bedford

Andre Nussenzweig

Meinrad Busslinger

Thomas Jenuwein

Affiliations

Soon will be listed here.

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.

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