Monomethylation of histone H4-lysine 20 is involved in chromosome structure and stability and is essential for mouse development.
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 G(2)/M phase, but the progeny were defective at the subsequent S and G(2)/M phases, exhibiting a delay in their cell cycle, accumulation at G(2)/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.
Oda
Hisanobu
H
Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.
Okamoto
Ikuhiro
I
Murphy
Niall
N
Chu
Jianhua
J
Price
Sandy M
SM
Shen
Michael M
MM
Torres-Padilla
Maria Elena
ME
Heard
Edith
E
Reinberg
Danny
D
D000818:Animals; D002453:Cell Cycle; D043171:Chromosomal Instability; D022004:Chromosome Structures; D004249:DNA Damage; D053595:Embryonic Stem Cells / Q000166:cytology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D007399:Interphase; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice / Q000254:growth & development*; D008817:Mice, Mutant Strains
D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D008239:Lysine; C529566:KMT5a protein, mouse