The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Dec 11

PMID 23219530

Citations 466

Authors

Stefanie Seisenberger

Simon Andrews

Felix Krueger

Julia Arand

Jorn Walter

Fatima Santos

Christian Popp

Bernard Thienpont

Wendy Dean

Wolf Reik

Affiliations

Soon will be listed here.

Abstract

Genome-wide DNA methylation reprogramming occurs in mouse primordial germ cells (PGCs) and preimplantation embryos, but the precise dynamics and biological outcomes are largely unknown. We have carried out whole-genome bisulfite sequencing (BS-Seq) and RNA-Seq across key stages from E6.5 epiblast to E16.5 PGCs. Global loss of methylation takes place during PGC expansion and migration with evidence for passive demethylation, but sequences that carry long-term epigenetic memory (imprints, CpG islands on the X chromosome, germline-specific genes) only become demethylated upon entry of PGCs into the gonads. The transcriptional profile of PGCs is tightly controlled despite global hypomethylation, with transient expression of the pluripotency network, suggesting that reprogramming and pluripotency are inextricably linked. Our results provide a framework for the understanding of the epigenetic ground state of pluripotency in the germline.

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References

Smith Z, Chan M, Mikkelsen T, Gu H, Gnirke A, Regev A . A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature. 2012; 484(7394):339-44. PMC: 3331945. DOI: 10.1038/nature10960. View

Wu H, DAlessio A, Ito S, Xia K, Wang Z, Cui K . Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature. 2011; 473(7347):389-93. PMC: 3539771. DOI: 10.1038/nature09934. View

Seki Y, Yamaji M, Yabuta Y, Sano M, Shigeta M, Matsui Y . Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice. Development. 2007; 134(14):2627-38. DOI: 10.1242/dev.005611. View

Sasaki H, Matsui Y . Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat Rev Genet. 2008; 9(2):129-40. DOI: 10.1038/nrg2295. View

Cloonan N, Forrest A, Kolle G, Gardiner B, Faulkner G, Brown M . Stem cell transcriptome profiling via massive-scale mRNA sequencing. Nat Methods. 2008; 5(7):613-9. DOI: 10.1038/nmeth.1223. View

Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo T . The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 2007; 450(7171):908-12. DOI: 10.1038/nature06397. View

Kano H, Godoy I, Courtney C, Vetter M, Gerton G, Ostertag E . L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes Dev. 2009; 23(11):1303-12. PMC: 2701581. DOI: 10.1101/gad.1803909. View

Tomizawa S, Kobayashi H, Watanabe T, Andrews S, Hata K, Kelsey G . Dynamic stage-specific changes in imprinted differentially methylated regions during early mammalian development and prevalence of non-CpG methylation in oocytes. Development. 2011; 138(5):811-20. PMC: 3035086. DOI: 10.1242/dev.061416. View

Lane N, Dean W, Erhardt S, Hajkova P, Surani A, Walter J . Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis. 2003; 35(2):88-93. DOI: 10.1002/gene.10168. View

10.

Yamazaki Y, Mann M, Lee S, Marh J, McCarrey J, Yanagimachi R . Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning. Proc Natl Acad Sci U S A. 2003; 100(21):12207-12. PMC: 218737. DOI: 10.1073/pnas.2035119100. View

11.

Yamaji M, Seki Y, Kurimoto K, Yabuta Y, Yuasa M, Shigeta M . Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat Genet. 2008; 40(8):1016-22. DOI: 10.1038/ng.186. View

12.

Karimi M, Goyal P, Maksakova I, Bilenky M, Leung D, Tang J . DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs. Cell Stem Cell. 2011; 8(6):676-87. PMC: 3857791. DOI: 10.1016/j.stem.2011.04.004. View

13.

Surani M, Hayashi K, Hajkova P . Genetic and epigenetic regulators of pluripotency. Cell. 2007; 128(4):747-62. DOI: 10.1016/j.cell.2007.02.010. View

14.

Santos F, Hendrich B, Reik W, Dean W . Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol. 2002; 241(1):172-82. DOI: 10.1006/dbio.2001.0501. View

15.

Lee J, Inoue K, Ono R, Ogonuki N, Kohda T, Kaneko-Ishino T . Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development. 2002; 129(8):1807-17. DOI: 10.1242/dev.129.8.1807. View

16.

Yoshimizu T, Sugiyama N, De Felice M, Yeom Y, Ohbo K, Masuko K . Germline-specific expression of the Oct-4/green fluorescent protein (GFP) transgene in mice. Dev Growth Differ. 2000; 41(6):675-84. DOI: 10.1046/j.1440-169x.1999.00474.x. View

17.

Laurent L, Wong E, Li G, Huynh T, Tsirigos A, Ong C . Dynamic changes in the human methylome during differentiation. Genome Res. 2010; 20(3):320-31. PMC: 2840979. DOI: 10.1101/gr.101907.109. View

18.

Hackett J, Reddington J, Nestor C, Dunican D, Branco M, Reichmann J . Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline. Development. 2012; 139(19):3623-32. PMC: 3436114. DOI: 10.1242/dev.081661. View

19.

Popp C, Dean W, Feng S, Cokus S, Andrews S, Pellegrini M . Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature. 2010; 463(7284):1101-5. PMC: 2965733. DOI: 10.1038/nature08829. View

20.

Vincent J, Li Z, Lee S, Liu X, Etter M, Diaz-Perez S . Single cell analysis facilitates staging of Blimp1-dependent primordial germ cells derived from mouse embryonic stem cells. PLoS One. 2011; 6(12):e28960. PMC: 3240638. DOI: 10.1371/journal.pone.0028960. View