Dynamic stage-specific changes in imprinted differentially methylated regions during early mammalian development and prevalence of non-CpG methylation in oocytes.
Mammalian imprinted genes are associated with differentially methylated regions (DMRs) that are CpG methylated on one of the two parental chromosomes. In mice, at least 21 DMRs acquire differential methylation in the germline and many of them act as imprint centres. We previously reported the physical extents of differential methylation at 15 DMRs in mouse embryos at 12.5 days postcoitum. To reveal the ontogeny of differential methylation, we determined and compared methylation patterns of the corresponding regions in sperm and oocytes. We found that the extent of the gametic DMRs differs significantly from that of the embryonic DMRs, especially in the case of paternal gametic DMRs. These results suggest that the gametic DMR sequences should be used to extract the features specifying methylation imprint establishment in the germline: from this analysis, we noted that the maternal gametic DMRs appear as unmethylated islands in male germ cells, which suggests a novel component in the mechanism of gamete-specific marking. Analysis of selected DMRs in blastocysts revealed dynamic changes in allelic methylation in early development, indicating that DMRs are not fully protected from the major epigenetic reprogramming events occurring during preimplantation development. Furthermore, we observed non-CpG methylation in oocytes, but not in sperm, which disappeared by the blastocyst stage. Non-CpG methylation was frequently found at maternally methylated DMRs as well as non-DMR regions, suggesting its prevalence in the oocyte genome. These results provide evidence for a unique methylation profile in oocytes and reveal the surprisingly dynamic nature of DMRs in the early embryo.
Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, Mishima, Japan.
Shin-ichi
S
Tomizawa
Hisato
H
Kobayashi
Toshiaki
T
Watanabe
Simon
S
Andrews
Kenichiro
K
Hata
Gavin
G
Kelsey
Hiroyuki
H
Sasaki
D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D016678:Genome; D018392:Genomic Imprinting / Q000235:genetics*; D008297:Male; D051379:Mice; D009865:Oocytes; D013094:Spermatozoa
Nature. 2007 Sep 13;449(7159):148-9
17851501
Nature. 2010 Apr 15;464(7291):1082-6
20393567
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):327-32
11756672
Nat Genet. 2002 Jan;30(1):92-6
11753386
Nat Genet. 2003 Sep;35(1):97-102
12937418
Nat Rev Genet. 2008 Feb;9(2):129-40
18197165
Hum Mol Genet. 2007 Oct 1;16(19):2272-80
17616512
Hum Mol Genet. 2009 Apr 15;18(8):1424-38
19174477
Nat Genet. 2002 Nov;32(3):426-31
12410230
Nat Genet. 1995 Apr;9(4):407-13
7795647
Nature. 2007 Aug 9;448(7154):714-7
17687327
Development. 2002 Apr;129(8):1983-93
11934864
Nature. 1997 Oct 16;389(6652):745-9
9338788
Genes Cells. 2006 Apr;11(4):353-61
16611239
Nature. 2007 Sep 13;449(7159):248-51
17713477
Nature. 2004 Jun 24;429(6994):900-3
15215868
Nat Genet. 1995 Jan;9(1):12-3
7704015
Cytogenet Genome Res. 2006;113(1-4):109-15
16575169
Nature. 2004 Sep 2;431(7004):96-9
15318244
Nucleic Acids Res. 2001 Sep 1;29(17):3506-12
11522819
PLoS Genet. 2010 Sep 09;6(9):e1001106
20838592
Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R47-58
15809273
Nature. 2009 Nov 19;462(7271):315-22
19829295
Cytogenet Genome Res. 2006;113(1-4):130-7
16575172
Dev Biol. 2001 Dec 15;240(2):585-98
11784085
Science. 2001 Aug 10;293(5532):1089-93
11498579
Nat Genet. 2004 Aug;36(8):894-9
15273687
Genome Res. 2004 Jun;14(6):1188-90
15173120
J Biol Chem. 2010 Aug 20;285(34):26114-20
20547484
Mol Cell Biol. 1997 Aug;17(8):4322-9
9234689
Mamm Genome. 2002 Nov;13(11):639-45
12461650
Mol Cell Biol. 2006 Nov;26(22):8347-56
16954379
Genes Dev. 1998 Dec 1;12(23):3693-702
9851976
Genomics. 2009 May;93(5):461-72
19200453
Genes Dev. 2009 Jan 1;23(1):105-17
19136628
Genomics. 2006 Sep;88(3):323-32
16690248
Genes Cells. 2010 Mar;15(3):169-79
20132320
Nat Rev Genet. 2001 Jan;2(1):21-32
11253064
Mol Cell. 2010 Apr 23;38(2):179-90
20417597
PLoS Genet. 2010 Sep 23;6(9):e1001134
20885785
EMBO J. 1993 Sep;12(9):3669-77
7504628
Nature. 2009 Sep 17;461(7262):415-8
19727073
Plant J. 2007 Aug;51(3):526-36
17559516
Genes Dev. 2008 Jun 15;22(12):1607-16
18559477
Mamm Genome. 1998 Jan;9(1):15-9
9434939
Mol Reprod Dev. 2005 Dec;72(4):430-6
16155959
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5237-42
10805783
Nat Genet. 1998 Jul;19(3):219-20
9662389
Nature. 1993 Apr 22;362(6422):751-5
8469285
BMC Bioinformatics. 2010 May 06;11:230
20459626
PLoS Genet. 2008 Aug 01;4(8):e1000145
18670629
J Biol Chem. 2005 May 20;280(20):20171-5
15778220