title: Haploinsufficiency, but not defective paternal 5mC oxidation, accounts for the developmental defects of maternal Tet3 knockouts.
abstract: Paternal DNA demethylation in mammalian zygotes is achieved through Tet3-mediated iterative oxidation of 5-methylcytosine (5mC) coupled with replication-dependent dilution. Tet3-mediated paternal DNA demethylation is believed to play important roles in mouse development given that Tet3 heterozygous embryos derived from Tet3-deficient oocytes exhibit embryonic sublethality. Here, we demonstrate that the sublethality phenotype of the Tet3 maternal knockout mice is caused by haploinsufficiency but not defective paternal 5mC oxidation. We found that Tet3 heterozygous progenies derived from heterozygous father or mother also exhibit sublethality. Importantly, wild-type embryos reconstituted with paternal pronuclei that bypassed 5mC oxidation develop and grow to adulthood normally. Genome-scale DNA methylation analysis demonstrated that hypermethylation in maternal Tet3 knockout embryos is largely diminished by the blastocyst stage. Our study thus reveals that Tet3-mediated paternal 5mC oxidation is dispensable for mouse development and suggests the existence of a compensatory mechanism for defective 5mC oxidation in preimplantation embryos.
authors: Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA.
authors: Azusa
authors: A
authors: Inoue
authors: Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA.
authors: Li
authors: L
authors: Shen
authors: Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA.
authors: Shogo
authors: S
authors: Matoba
authors: Howard Hughes Medical Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard Medical School, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: yzhang@genetics.med.harvard.edu.
authors: Yi
authors: Y
authors: Zhang
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism*; D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism*; D049308:Dioxygenases; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000378:metabolism*; D015053:Zygote / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D044503:5-Methylcytosine; D049308:Dioxygenases; C551915:Tet3 protein, mouse
references: Nature. 2012 Mar 28;484(7394):339-44
references: 22456710
references: Epigenetics Chromatin. 2008 Nov 03;1(1):8
references: 19014417
references: Cell. 2013 Jul 18;154(2):452-64
references: 23870131
references: Cell. 2013 May 9;153(4):910-8
references: 23643243
references: Nature. 2014 Jul 31;511(7511):606-10
references: 25079557
references: Nat Rev Genet. 2008 Feb;9(2):129-40
references: 18197165
references: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3642-7
references: 21321204
references: Nat Commun. 2011;2:241
references: 21407207
references: Science. 2011 Oct 14;334(6053):194
references: 21940858
references: Nat Rev Mol Cell Biol. 2010 Sep;11(9):607-20
references: 20683471
references: Nat Rev Genet. 2013 Mar;14(3):204-20
references: 23400093
references: Genes Dev. 2008 Jun 15;22(12):1607-16
references: 18559477
references: Cell Stem Cell. 2014 Oct 2;15(4):393-394
references: 25280211
references: Cell Stem Cell. 2014 Oct 2;15(4):459-471
references: 25280220
references: Epigenetics. 2011 Aug;6(8):987-93
references: 21725201
references: Nature. 2014 Jul 31;511(7511):611-5
references: 25079558
references: Nature. 2011 Sep 04;477(7366):606-10
references: 21892189
references: Nat Rev Mol Cell Biol. 2013 Jun;14(6):341-56
references: 23698584
references: Int J Dev Biol. 2010;54(8-9):1323-8
references: 20563995
references: Cell. 2014 Jan 16;156(1-2):45-68
references: 24439369
references: Nature. 2000 Feb 3;403(6769):501-2
references: 10676950
references: Curr Biol. 2004 Apr 6;14(7):R266-7
references: 15062117
references: Nature. 2013 Oct 24;502(7472):472-9
references: 24153300
references: Curr Biol. 2000 Apr 20;10(8):475-8
references: 10801417
references: Curr Protoc Mol Biol. 2012 Apr;Chapter 2:Unit 2.13.1-3
references: 22470062
references: Int J Dev Biol. 2008;52(2-3):295-8
references: 18311720
references: Int J Dev Biol. 2007;51(8):707-14
references: 17939117
references: Hum Reprod. 2008 Jun;23(6):1377-84
references: 18367455
references: Genes Dev. 1998 Jul 15;12(14):2108-13
references: 9679055
references: Cell Res. 2012 Dec;22(12):1640-9
references: 23184059
references: Cell Res. 2011 Dec;21(12):1670-6
references: 22124233
references: Curr Opin Cell Biol. 2013 Jun;25(3):281-8
references: 23510682
references: Cell. 2014 May 8;157(4):979-991
references: 24813617
references: Development. 2012 Jan;139(1):15-31
references: 22147951
references: Genes Dev. 2014 Apr 15;28(8):812-28
references: 24736841
references: Cell Stem Cell. 2014 Oct 2;15(4):447-459
references: 25220291