title: Dynamics of 5-methylcytosine and 5-hydroxymethylcytosine during germ cell reprogramming.
abstract: Previous studies have revealed that mouse primordial germ cells (PGCs) undergo genome-wide DNA methylation reprogramming to reset the epigenome for totipotency. However, the precise 5-methylcytosine (5mC) dynamics and its relationship with the generation of 5-hydroxymethylcytosine (5hmC) are not clear. Here we analyzed the dynamics of 5mC and 5hmC during PGC reprograming and germ cell development. Unexpectedly, we found a specific period (E8.5-9.5) during which both 5mC and 5hmC levels are low. Subsequently, 5hmC levels increase reaching its peak at E11.5 and gradually decrease until E13.5 likely by replication-dependent dilution. Interestingly, 5hmC is enriched in chromocenters during this period. While this germ cell-specific 5hmC subnuclear localization pattern is maintained in female germ cells even in mature oocytes, such pattern is gradually lost in male germ cells as mitotic proliferation resumes during the neonatal stage. Pericentric 5hmC plays an important role in silencing major satellite repeat, especially in female PGCs. Global transcriptome analysis by RNA-seq revealed that the great majority of differentially expressed genes from E9.5 to 13.5 are upregulated in both male and female PGCs. Although only female PGCs enter meiosis during the prenatal stage, meiosis-related and a subset of imprinted genes are significantly upregulated in both male and female PGCs at E13.5. Thus, our study not only reveals the dynamics of 5mC and 5hmC during PGC reprogramming and germ cell development, but also their potential role in epigenetic reprogramming and transcriptional regulation of meiotic and imprinted genes.
authors: Howard Hughes Medical Institute, WAB-149G, 200 Longwood Av., Boston, MA 02115, USA.
authors: Shinpei
authors: S
authors: Yamaguchi
authors: Kwonho
authors: K
authors: Hong
authors: Rui
authors: R
authors: Liu
authors: Azusa
authors: A
authors: Inoue
authors: Li
authors: L
authors: Shen
authors: Kun
authors: K
authors: Zhang
authors: Yi
authors: Y
authors: Zhang
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism* / Q000031:analogs & derivatives; D000818:Animals; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D018392:Genomic Imprinting / Q000235:genetics / Q000502:physiology; D005854:Germ Cells / Q000378:metabolism*; D006570:Heterochromatin / Q000378:metabolism; D008297:Male; D051379:Mice
chemical_list: D006570:Heterochromatin; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine
references: Genes Dev. 2011 Dec 1;25(23):2436-52
references: 22156206
references: Nat Cell Biol. 2006 Jun;8(6):623-30
references: 16699504
references: Chromosome Res. 2012 Oct;20(7):837-48
references: 23111490
references: Genome Res. 2012 Apr;22(4):633-41
references: 22357612
references: PLoS Genet. 2007 Jul;3(7):e116
references: 17676999
references: Nat Rev Genet. 2008 Feb;9(2):129-40
references: 18197165
references: Nat Biotechnol. 2012 Aug;30(8):777-82
references: 22820318
references: Trends Genet. 2012 Apr;28(4):164-74
references: 22386917
references: Science. 2011 Oct 14;334(6053):194
references: 21940858
references: Cancer Res. 2007 Feb 1;67(3):946-50
references: 17283125
references: Science. 2011 Sep 2;333(6047):1300-3
references: 21778364
references: PLoS Genet. 2011 Jun;7(6):e1002154
references: 21731508
references: Development. 2002 Apr;129(8):1807-17
references: 11934847
references: Nature. 2010 Feb 25;463(7284):1101-5
references: 20098412
references: Science. 2011 Sep 2;333(6047):1303-7
references: 21817016
references: Development. 2012 Oct;139(19):3623-32
references: 22949617
references: Mol Cell Endocrinol. 2010 Jul 8;323(1):76-93
references: 20036311
references: Nature. 2010 Aug 26;466(7310):1129-33
references: 20639862
references: Genes Dev. 2008 Jun 15;22(12):1617-35
references: 18559478
references: Mech Dev. 2002 Sep;117(1-2):15-23
references: 12204247
references: Development. 2006 Sep;133(17):3411-8
references: 16887828
references: Science. 2013 Jan 25;339(6118):448-52
references: 23223451
references: Mol Cell. 2012 Dec 28;48(6):849-62
references: 23219530
references: Nature. 2012 Dec 20;492(7429):443-7
references: 23151479
references: Science. 2009 May 15;324(5929):930-5
references: 19372391
references: Cell. 2011 Jul 8;146(1):67-79
references: 21722948
references: Cell Res. 2011 Dec;21(12):1670-6
references: 22124233
references: Reproduction. 2010 Jun;139(6):931-42
references: 20371640
references: Dev Biol. 2005 Feb 15;278(2):440-58
references: 15680362
references: Nature. 2008 Apr 17;452(7189):877-81
references: 18354397
references: Nat Rev Mol Cell Biol. 2010 Sep;11(9):607-20
references: 20683471
references: Development. 2012 Jan;139(1):15-31
references: 22147951
references: Science. 2010 Jul 2;329(5987):78-82
references: 20595612
references: Biol Reprod. 2009 Apr;80(4):804-12
references: 19129513
references: EMBO J. 2013 Feb 6;32(3):340-53
references: 23241950