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Specification and epigenetic programming of the human germ line

Key Points

  • Regulation of pluripotency and early post-implantation embryonic development have diverged between humans and mice, which might affect the mechanism of primordial germ cell (PGC) specification.

  • Specification of human and mouse PGCs occurs in response to extrinsic signals, including bone morphogenetic protein 2 (BMP2) and BMP4.

  • Models of human PGC specification from pluripotent stem cells suggest that human PGCs originate from mesodermal precursors at the posterior epiblast during the onset of gastrulation, whereas mouse PGCs originate from the pre-gastrulation epiblast.

  • The gene regulatory network for PGC specification and maintenance in humans and mice has diverged. Notably, SRY-box 17 (SOX17), a key endoderm specifier, is critical for PGC specification in humans but not in mice.

  • PGCs undergo genome-wide DNA demethylation, which erases parental epigenetic memories and facilitates germ cell differentiation in humans and mice.

  • Repressive histone modifications might safeguard PGC genome stability during global DNA demethylation.

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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Figure 1: Cycle of human germline development.
Figure 2: Signalling for mammalian germline induction.
Figure 3: Reconstitution of mouse and human PGC specification in vitro.
Figure 4: Gene regulatory network models for mouse and human PGC specification.
Figure 5: Epigenetic reprogramming in mouse and human PGCs.

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Acknowledgements

The authors thank J. Hackett for reading of the manuscript and members of the Surani laboratory for helpful discussions. Our work was funded by a Wellcome Trust Investigator Award to M.A.S, and by a Britain Israel Research and Academic Exchange (BIRAX) Initiative and a Croucher Cambridge International Scholarship to W.W.C.T. Research at the Gurdon Institute is funded by a core grant from the Wellcome Trust (092096) and Cancer Research UK (C6946/A14492). The authors apologize to colleagues whose work could not be cited owing to length limitations.

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Glossary

Totipotent

The ability of a cell to give rise to all cell types (both embryonic and extra-embryonic) of an organism.

Pluripotent epiblast cells

Cells derived from the inner cell mass of a blastocyst that give rise to all lineages of the embryo proper.

Allantois

A membranous sac that develops from the mesoderm (in mice) or the hindgut endoderm (in humans) during early embryonic development. The allantois contributes to the formation of the umbilical cord and placenta.

Genomic imprint

An epigenetic phenomenon that results in monoallelic gene expression in a parent-of-origin-dependent manner.

Gastrulation

The developmental process in which the three germ layers (that is, the ectoderm, mesoderm and definitive endoderm) of the embryo are formed.

Primitive streak

A structure at the posterior end of the embryo where epiblast cells ingress to form the mesoderm and the definitive endoderm. Formation of the primitive streak is the first visible sign of gastrulation.

Nodal signalling

A signal transduction pathway that is essential for the formation of the mesoderm and the endoderm, and for axis determination in vertebrates. Nodal signalling is activated by transforming growth factor-β (TGFβ) family factors Activin and Nodal, and is transduced by SMAD2 and SMAD3.

Trophoblast

The outermost layer of extra-embryonic tissues that attaches the embryo to the uterine wall and forms the placenta.

Pluripotent states

Pluripotency refers to the ability of a cell to differentiate into any cell of the three germ layers in the embryo proper. The pre-implantation epiblast represents a naive pluripotent state, whereas the post-implantation epiblast (poised for lineage differentiation) represents a 'primed' pluripotent state.

Lineage specifiers

Transcription factors that direct competent cells to differentiate into a specific cell lineage.

Inner cell mass

(ICM). A compact mass of cells located at the embryonic pole of the blastocyst. The ICM gives rise to the epiblast and the hypoblast, which form the embryo proper and the yolk sac, respectively.

Retrotransposons

DNA elements that can amplify themselves in the genome. During the process of retrotransposition, retrotransposon DNA is first transcribed into RNA, then reverse transcribed into DNA, followed by insertion into a new genomic site.

Krüpple-associated box zinc-finger protein

(KRAB-ZFP). The largest individual family of transcriptional repressors in mammals. KRAB-ZFPs contain DNA-binding C2H2 zinc-fingers and a KRAB domain that interacts with the KRAB-associated protein 1 (KAP1) co-repressor complex for epigenetic silencing.

Transgenerational epigenetic inheritance

(TEI). Transmission of epigenetic information through the germ line that affects phenotypic traits in more than one generation without changes in DNA sequence.

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Tang, W., Kobayashi, T., Irie, N. et al. Specification and epigenetic programming of the human germ line. Nat Rev Genet 17, 585–600 (2016). https://doi.org/10.1038/nrg.2016.88

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