title: The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure.
abstract: 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.
authors.affiliation: Epigenetics Program, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Brendan
authors.initials: B
authors.lastname: Jones
authors.forename: Hui
authors.initials: H
authors.lastname: Su
authors.forename: Audesh
authors.initials: A
authors.lastname: Bhat
authors.forename: Hong
authors.initials: H
authors.lastname: Lei
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Bajko
authors.forename: Sarah
authors.initials: S
authors.lastname: Hevi
authors.forename: Gretchen A
authors.initials: GA
authors.lastname: Baltus
authors.forename: Shilpa
authors.initials: S
authors.lastname: Kadam
authors.forename: Huili
authors.initials: H
authors.lastname: Zhai
authors.forename: Reginald
authors.initials: R
authors.lastname: Valdez
authors.forename: Susana
authors.initials: S
authors.lastname: Gonzalo
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: En
authors.initials: E
authors.lastname: Li
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen
mesh_terms: 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
chemical_list: D006570:Heterochromatin; D006657:Histones; C481527:Dot1l protein, mouse; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine
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