Specification and Epigenetic Programming of the Human Germ Line

Overview

Journal Nat Rev Genet

Specialty Genetics

Date 2016 Aug 31

PMID 27573372

Citations 191

Authors

Walfred W C Tang

Toshihiro Kobayashi

Naoko Irie

Sabine Dietmann

M Azim Surani

Affiliations

Soon will be listed here.

Abstract

Primordial germ cells (PGCs), the precursors of sperm and eggs, are established in perigastrulation-stage embryos in mammals. Signals from extra-embryonic tissues induce a unique gene regulatory network in germline-competent cells for PGC specification. This network also initiates comprehensive epigenome resetting, including global DNA demethylation and chromatin reorganization. Mouse germline development has been studied extensively, but the extent to which such knowledge applies to humans was unclear. Here, we review the latest advances in human PGC specification and epigenetic reprogramming. The overall developmental dynamics of human and mouse germline cells appear to be similar, but there are crucial mechanistic differences in PGC specification, reflecting divergence in the regulation of pluripotency and early development.

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References

Kee K, Gonsalves J, Clark A, Pera R . Bone morphogenetic proteins induce germ cell differentiation from human embryonic stem cells. Stem Cells Dev. 2007; 15(6):831-7. DOI: 10.1089/scd.2006.15.831. View

Johnson A, Alberio R . Primordial germ cells: the first cell lineage or the last cells standing?. Development. 2015; 142(16):2730-9. PMC: 4550962. DOI: 10.1242/dev.113993. View

Chia N, Chan Y, Feng B, Lu X, Orlov Y, Moreau D . A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity. Nature. 2010; 468(7321):316-20. DOI: 10.1038/nature09531. View

Chuva de Sousa Lopes S, Hayashi K, Shovlin T, Mifsud W, Surani M, Mclaren A . X chromosome activity in mouse XX primordial germ cells. PLoS Genet. 2008; 4(2):e30. PMC: 2233679. DOI: 10.1371/journal.pgen.0040030. View

Clark A, Bodnar M, Fox M, Rodriquez R, Abeyta M, Firpo M . Spontaneous differentiation of germ cells from human embryonic stem cells in vitro. Hum Mol Genet. 2004; 13(7):727-39. DOI: 10.1093/hmg/ddh088. View

Gkountela S, Li Z, Vincent J, Zhang K, Chen A, Pellegrini M . The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation. Nat Cell Biol. 2012; 15(1):113-22. PMC: 3786872. DOI: 10.1038/ncb2638. View

Gkountela S, Zhang K, Shafiq T, Liao W, Hargan-Calvopina J, Chen P . DNA Demethylation Dynamics in the Human Prenatal Germline. Cell. 2015; 161(6):1425-36. PMC: 4458157. DOI: 10.1016/j.cell.2015.05.012. View

Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T . Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2007; 26(1):101-6. DOI: 10.1038/nbt1374. View

Ma Z, Swigut T, Valouev A, Rada-Iglesias A, Wysocka J . Sequence-specific regulator Prdm14 safeguards mouse ESCs from entering extraembryonic endoderm fates. Nat Struct Mol Biol. 2010; 18(2):120-7. DOI: 10.1038/nsmb.2000. View

10.

Valdez Magana G, Rodriguez A, Zhang H, Webb R, Alberio R . Paracrine effects of embryo-derived FGF4 and BMP4 during pig trophoblast elongation. Dev Biol. 2014; 387(1):15-27. DOI: 10.1016/j.ydbio.2014.01.008. View

11.

Takashima Y, Guo G, Loos R, Nichols J, Ficz G, Krueger F . Resetting transcription factor control circuitry toward ground-state pluripotency in human. Cell. 2014; 158(6):1254-1269. PMC: 4162745. DOI: 10.1016/j.cell.2014.08.029. View

12.

Kehler J, Tolkunova E, Koschorz B, Pesce M, Gentile L, Boiani M . Oct4 is required for primordial germ cell survival. EMBO Rep. 2004; 5(11):1078-83. PMC: 1299174. DOI: 10.1038/sj.embor.7400279. View

13.

Toyooka Y, Tsunekawa N, Akasu R, Noce T . Embryonic stem cells can form germ cells in vitro. Proc Natl Acad Sci U S A. 2003; 100(20):11457-62. PMC: 208779. DOI: 10.1073/pnas.1932826100. View

14.

Tsumura A, Hayakawa T, Kumaki Y, Takebayashi S, Sakaue M, Matsuoka C . Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells. 2006; 11(7):805-14. DOI: 10.1111/j.1365-2443.2006.00984.x. View

15.

Bohacek J, Mansuy I . Molecular insights into transgenerational non-genetic inheritance of acquired behaviours. Nat Rev Genet. 2015; 16(11):641-52. DOI: 10.1038/nrg3964. View

16.

Ying Y, Liu X, Marble A, Lawson K, Zhao G . Requirement of Bmp8b for the generation of primordial germ cells in the mouse. Mol Endocrinol. 2000; 14(7):1053-63. DOI: 10.1210/mend.14.7.0479. View

17.

Liu P, Wakamiya M, Shea M, Albrecht U, Behringer R, Bradley A . Requirement for Wnt3 in vertebrate axis formation. Nat Genet. 1999; 22(4):361-5. DOI: 10.1038/11932. View

18.

Jacobs F, Greenberg D, Nguyen N, Haeussler M, Ewing A, Katzman S . An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature. 2014; 516(7530):242-5. PMC: 4268317. DOI: 10.1038/nature13760. View

19.

Kerr C, Hill C, Blumenthal P, Gearhart J . Expression of pluripotent stem cell markers in the human fetal testis. Stem Cells. 2007; 26(2):412-21. DOI: 10.1634/stemcells.2007-0605. View

20.

Magnusdottir E, Dietmann S, Murakami K, Gunesdogan U, Tang F, Bao S . A tripartite transcription factor network regulates primordial germ cell specification in mice. Nat Cell Biol. 2013; 15(8):905-15. PMC: 3796875. DOI: 10.1038/ncb2798. View