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Molecular and Cellular Biology, April 2009, p. 2278-2295, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01768-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Monomethylation of Histone H4-Lysine 20 Is Involved in Chromosome Structure and Stability and Is Essential for Mouse Development{triangledown}

Hisanobu Oda,1 Ikuhiro Okamoto,2 Niall Murphy,2 Jianhua Chu,3,4 Sandy M. Price,3 Michael M. Shen,3,4 Maria Elena Torres-Padilla,5 Edith Heard,2* and Danny Reinberg1,6*

Howard Hughes Medical Institute,6 Department of Biochemistry, New York University School of Medicine, 522 First Avenue, New York, New York 10016,1 Mammalian Developmental Epigenetics Group, CNRS UMR218, Nuclear Dynamics and Genome Stability, Institute Curie, 26 Rue d'Ulm, 75248 Paris Cedex 05, France,2 Center for Advanced Biotechnology and Medicine, Department of Pediatrics, UMDNJ—Robert Wood Johnson Medical School, Piscataway, New Jersey 08854,3 Departments of Medicine and Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032,4 Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR 7104, CNRS, INSERM, ULP, CU de Strasbourg, 67404 Illkirch, France5

Received 18 November 2008/ Returned for modification 15 December 2008/ Accepted 29 January 2009

PR-Set7/Set8/KMT5A is the sole enzyme known to catalyze monomethylation of histone H4 lysine 20 (H4K20) and is present only in multicellular organisms that compact a large fraction of their DNA. We found that mouse embryos that are homozygous null mutants for the gene PR-Set7 display early embryonic lethality prior to the eight-cell stage. Death was due to the absence of PR-Set7 catalytic activity, since microinjection of the wild type, but not a catalytically inactive version, into two-cell embryos rescued the phenotype. A lack of PR-Set7 activity resulted not only in depletion of H4K20me1 but also in reduced levels of the H4K20me2/3 marks catalyzed by the Suv4-20h1/h2 enzymes, implying that H4K20me1 may be essential for the function of these enzymes to ensure the dimethylated and trimethylated states. Embryonic stem cells that were inducibly deleted for PR-Set7 passed through an initial G2/M phase, but the progeny were defective at the subsequent S and G2/M phases, exhibiting a delay in their cell cycle, accumulation at G2/M, massive DNA damage, and improper mitotic chromosome condensation. Cell cycle analysis after synchronization indicated that the defects were a consequence of decreased H4K20me1 due to the absence of PR-Set7. Most importantly, the lack of H4K20me1 also resulted in defects in chromosome condensation in interphase nuclei. These results demonstrate the critical role of H4K20 monomethylation in mammals in a developmental context.

* Corresponding author. Mailing address for Danny Reinberg: Howard Hughes Medical Institute, NYU School of Medicine—Smilow Research Center, Biochemistry Department, 522 First Avenue, 2nd Floor, Room 211, New York, NY 10016. Phone: (212) 263-9036. Fax: (212) 263-9040. E-mail: reinbd01{at}nyumc.org. Mailing address for Edith Heard: CNRS UMR3215, INSERM U934, Institut Curie, 26 Rue d'Ulm, 75248 Paris Cedex 05, France. Phone: 33 1 56 24 66 91. Fax: 33 1 46 33 30 16. E-mail: Edith.Heard{at}curie.fr

{triangledown} Published ahead of print on 17 February 2009.

Molecular and Cellular Biology, April 2009, p. 2278-2295, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01768-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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