The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure.
Dot1 is an evolutionarily conserved histone methyltransferase specific for lysine 79 of histone H3 (H3K79). In Saccharomyces cerevisiae, Dot1-mediated H3K79 methylation is associated with telomere silencing, meiotic checkpoint control, and DNA damage response. The biological function of H3K79 methylation in mammals, however, remains poorly understood. Using gene targeting, we generated mice deficient for Dot1L, the murine Dot1 homologue. Dot1L-deficient embryos show multiple developmental abnormalities, including growth impairment, angiogenesis defects in the yolk sac, and cardiac dilation, and die between 9.5 and 10.5 days post coitum. To gain insights into the cellular function of Dot1L, we derived embryonic stem (ES) cells from Dot1L mutant blastocysts. Dot1L-deficient ES cells show global loss of H3K79 methylation as well as reduced levels of heterochromatic marks (H3K9 di-methylation and H4K20 tri-methylation) at centromeres and telomeres. These changes are accompanied by aneuploidy, telomere elongation, and proliferation defects. Taken together, these results indicate that Dot1L and H3K79 methylation play important roles in heterochromatin formation and in embryonic development.
Jones
Brendan
B
Epigenetics Program, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States of America.
Su
Hui
H
Bhat
Audesh
A
Lei
Hong
H
Bajko
Jeffrey
J
Hevi
Sarah
S
Baltus
Gretchen A
GA
Kadam
Shilpa
S
Zhai
Huili
H
Valdez
Reginald
R
Gonzalo
Susana
S
Zhang
Yi
Y
Li
En
E
Chen
Taiping
T
D000782:Aneuploidy; D000818:Animals; D002503:Centromere / Q000378:metabolism; D004622:Embryo, Mammalian / Q000201:enzymology*; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D006570:Heterochromatin / Q000737:chemistry / Q000378:metabolism*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D011496:Protein Methyltransferases / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism
D006570:Heterochromatin; D006657:Histones; C481527:Dot1l protein, mouse; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine
Mol Cell Biol. 2005 Oct;25(19):8430-43
16166626
Differentiation. 2001 Oct;68(4-5):175-85
11776470
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1820-5
12574507
Mol Biol Cell. 2000 Oct;11(10):3601-15
11029058
Nat Cell Biol. 2006 Apr;8(4):416-24
16565708
Nat Genet. 2002 Oct;32(2):273-9
12244315
Cell. 2001 Nov 2;107(3):323-37
11701123
Cell Mol Life Sci. 2003 Nov;60(11):2303-18
14625677
Blood. 1996 Nov 15;88(10):3720-30
8916936
Genes Dev. 2004 Jun 1;18(11):1251-62
15145825
Mol Cell. 2003 Dec;12(6):1577-89
14690609
Cell. 2005 Apr 22;121(2):167-78
15851025
Cell. 2007 Feb 23;128(4):693-705
17320507
Genetics. 1998 Oct;150(2):613-32
9755194
Nat Genet. 2004 Jan;36(1):94-9
14702045
Nat Cell Biol. 2001 Feb;3(2):114-20
11175742
Science. 2001 Aug 10;293(5532):1074-80
11498575
J Cell Sci. 2004 May 15;117(Pt 12):2491-501
15128874
Mol Cell. 2006 Aug;23(4):497-507
16916638
Nat Genet. 2000 Dec;26(4):447-50
11101843
Cell. 2002 Jun 14;109(6):745-56
12086673
Curr Biol. 2002 Jun 25;12(12):1052-8
12123582
J Biol Chem. 1999 Dec 17;274(51):36585-91
10593959
J Cell Biol. 2007 Sep 10;178(6):925-36
17846168
Nat Cell Biol. 2006 Sep;8(9):1017-24
16921363
Genes Dev. 2002 Jun 15;16(12):1518-27
12080090
Mol Cell Biol. 2008 Apr;28(8):2825-39
18285465
Oncogene. 2002 Jan 21;21(4):553-63
11850780
Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R191-6
16244317
Mol Cell Biol. 2004 Mar;24(6):2478-86
14993285
Cell. 1997 Dec 26;91(7):1021-32
9428524
Development. 1996 Oct;122(10):3195-205
8898232
Annu Rev Biophys Biomol Struct. 2005;34:267-94
15869391
Mol Cell Biol. 2003 Aug;23(16):5594-605
12897133