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

Gunnar Schotta; Roopsha Sengupta; Stefan Kubicek; Stephen Malin; Monika Kauer; Elsa Callén; Arkady Celeste; Michaela Pagani; Susanne Opravil; Inti A. De La Rosa-Velazquez; Alexsandra Espejo; Mark T. Bedford; André Nussenzweig; Meinrad Busslinger; Thomas Jenuwein

doi:10.1101/gad.476008

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

Gunnar Schotta, Roopsha Sengupta, Stefan Kubicek, Stephen Malin, Monika Kauer, Elsa Callén, Arkady Celeste, Michaela Pagani, Susanne Opravil, Inti A. De La Rosa-Velazquez, Alexsandra Espejo, Mark T. Bedford, André Nussenzweig, Meinrad Busslinger, Thomas Jenuwein

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342 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2048-2061
Number of pages	14
Journal	Genes and Development
Volume	22
Issue number	15
DOIs	https://doi.org/10.1101/gad.476008
State	Published - Aug 1 2008

Keywords

B-cell differentiation
Class-switch recombination
DNA repair
Genome integrity
H4K20 methylation
Suv4-20h enzymes

ASJC Scopus subject areas

Genetics
Developmental Biology

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Schotta, G., Sengupta, R., Kubicek, S., Malin, S., Kauer, M., Callén, E., Celeste, A., Pagani, M., Opravil, S., De La Rosa-Velazquez, I. A., Espejo, A., Bedford, M. T., Nussenzweig, A., Busslinger, M., & Jenuwein, T. (2008). A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes and Development, 22(15), 2048-2061. https://doi.org/10.1101/gad.476008

Schotta, G, Sengupta, R, Kubicek, S, Malin, S, Kauer, M, Callén, E, Celeste, A, Pagani, M, Opravil, S, De La Rosa-Velazquez, IA, Espejo, A , Bedford, MT, Nussenzweig, A, Busslinger, M & Jenuwein, T 2008, 'A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse', Genes and Development, vol. 22, no. 15, pp. 2048-2061. https://doi.org/10.1101/gad.476008

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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 = "B-cell differentiation, Class-switch recombination, DNA repair, Genome integrity, H4K20 methylation, Suv4-20h enzymes",

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AU - Schotta, Gunnar

AU - Sengupta, Roopsha

AU - Kubicek, Stefan

AU - Malin, Stephen

AU - Kauer, Monika

AU - Callén, Elsa

AU - Celeste, Arkady

AU - Pagani, Michaela

AU - Opravil, Susanne

AU - De La Rosa-Velazquez, Inti A.

AU - Espejo, Alexsandra

AU - Bedford, Mark T.

AU - Nussenzweig, André

AU - Busslinger, Meinrad

AU - Jenuwein, Thomas

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N2 - 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.

AB - 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.

KW - B-cell differentiation

KW - Class-switch recombination

KW - DNA repair

KW - Genome integrity

KW - H4K20 methylation

KW - Suv4-20h enzymes

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

Abstract

Keywords

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