REVIEWS Paternal trol of meiosis Imprinting Germ-cell specification Birth/prepuberty/adult ression and activation Suppression of somatic genes Transposon repression PGC founder population PGCs zygote MIll oocyte/egg PGCs settled in gonad Onset of Sex differentiation ully grown oocyte E6.0 Ovulation reprogramming Imprint erasure E17.5 Birth/ prepuberty/adult X-chromosome reactivation Figure 1 Germ cell development and associated epigenetic events in mice. Chronology of mouse germ cell development and the main epigenetic events that occur. PGCs(primordial germ cells) first emerge at embryonic day 7. 25(E7. 25)as a cluster of about 20 cells. Subsequently, they rapidly proliferate with an average doubling time of approximately 16 hours Before they stop dividing at E13.5, their number reaches up to about 26,000 MSCl, meiotic sex-chromosome inactivation DNA methylation A covalent modification that epigenetic changes ar might be important suppression. PGC-like cel dinucelotides in the vertebrate contributions to germ-cell-specific functions at each in Blimpl-null embryos have aberrant expression of the nome.It is catalysed by stage. Understanding the epigenetic changes that take Hox genes6, which are normally repressed in PGCs. This DNA methyltransferases place during germ-cell development has important suggests that BLIMPI is crucial for suppression of the transcription directly by resses implications for animal cloning, assisted reproductive somatic programme, which might ensure that the PGC echnologies and human health precursors and nascent PGCs are restricted to the rganisms such as Caenorhabditis ele specific transcription factors, Germ-cell specification and differentiation and Drosophila melanogaster, this repression involves nd indirectly by recruiting Determination and maintenance of the germ-cell fate. global inhibition of RNA polymerase II (RNAPII) In post-implantation mammalian embryos, a popula- dependent transcription 7-19. In D. melanogaster, the and their associated repressive tion of pluripotent cells in the epiblast gives rise to pri- pole cells that develop into PGCs also have reduced chromatin-remodelling ctivities mondial germ cells(PGCs), the fate of which is specified levels of histone H3 lysine 4 methylation(H3K4me), by tissue interaction during gastrulation. In mice, PGCs a mark that is associated with the permissive(active) Histone modifications first emerge inside the extra-embryonic mesoderm at state, and are enriched in H3K9me, a mark that is translational modifications the posterior end of the primitive streak as a cluster of associated with repression, suggesting a role for epi that alter their interactions cells at embryonic day 7.25(E7. 25)(REFS 7-9)(FIG. 1). genetic modifications in suppressing the somatic pro Before the final specification of PGCs, their precursors gramme. Here, maternally inherited molecules such roteins. In particular, the tails are induced within the proximal epiblast cell popula- as the products of gcl (germ-cell-less)212, pgc(polar of histones H3 and H4 can b tion by signals from the adjacent extra-embryonic ecto- granule component)2.2and nanos u are involved in esidues. Modifications of dermo-ls. A transcriptional regulator, B-lymphocyte the transcriptional quiescence. Therefore, suppres- the tail include methylation, maturation-induced protein 1(BLIMPI, also known as sion of somatic differentiation through transcriptional etylation, phosphorylation PR-domain-containing 1), is expressed specifically in regulation might be an evolutionarily conserved theme the precursor cells as early as E6. 25(REF. 16), and this for germ-cell specification. However, as RNAPII is processes, including gene molecule is essential for PGC specification learly active in nascent PGCs in mice, the molecules The PGCprecursors need to suppress the somaticgene- and mechanisms that regulate the process might differ pression programme, and epigenetic modifications between species www.nature.com/reviews/genetics @2008 Nature Publishing GroupDNA methylation A covalent modification that occurs predominantly at CpG dinucelotides in the vertebrate genome. It is catalysed by DNA methyltransferases and converts cytosines to 5‑methylcytosines. It represses transcription directly by inhibiting the binding of specific transcription factors, and indirectly by recruiting methyl-CpG-binding proteins and their associated repressive chromatin-remodelling activities. Histone modifications Histones undergo post￾translational modifications that alter their interactions with DNA and nuclear proteins. In particular, the tails of histones H3 and H4 can be covalently modified at several residues. Modifications of the tail include methylation, acetylation, phosphorylation and ubiquitylation, and influence several biological processes, including gene expression, DNA repair and chromosome condensation. and we describe the epigenetic changes and their contributions to germ-cell-specific functions at each stage. Understanding the epigenetic changes that take place during germ-cell development has important implications for animal cloning, assisted reproductive technologies and human health. Germ-cell specification and differentiation Determination and maintenance of the germ-cell fate. In post-implantation mammalian embryos, a popula￾tion of pluripotent cells in the epiblast gives rise to pri￾mordial germ cells (PGCs), the fate of which is specified by tissue interaction during gastrulation. In mice, PGCs first emerge inside the extra-embryonic mesoderm at the posterior end of the primitive streak as a cluster of cells at embryonic day 7.25 (E7.25) (REFS 7–9) (FIG. 1). Before the final specification of PGCs, their precursors are induced within the proximal epiblast cell popula￾tion by signals from the adjacent extra-embryonic ecto￾derm10–15. A transcriptional regulator, B‑lymphocyte maturation-induced protein 1 (BLIMP1, also known as PR-domain-containing 1), is expressed specifically in the precursor cells as early as E6.25 (REF. 16), and this molecule is essential for PGC specification. The PGC precursors need to suppress the somatic gene￾expression programme, and epigenetic modifications might be important for this suppression. PGC-like cells in Blimp1-null embryos have aberrant expression of the Hox genes16, which are normally repressed in PGCs. This suggests that BLIMP1 is crucial for suppression of the somatic programme, which might ensure that the PGC precursors and nascent PGCs are restricted to the germ￾cell fate. In organisms such as Caenorhabditis elegans and Drosophila melanogaster, this repression involves global inhibition of RNA polymerase II (RNAPII)- dependent transcription17–19. In D. melanogaster, the pole cells that develop into PGCs also have reduced levels of histone H3 lysine 4 methylation (H3K4me), a mark that is associated with the permissive (active) state, and are enriched in H3K9me, a mark that is associated with repression, suggesting a role for epi￾genetic modifications in suppressing the somatic pro￾gramme20. Here, maternally inherited molecules such as the products of gcl (germ-cell-less)21,22, pgc (polar granule component)23,24 and nanos20,25 are involved in the transcriptional quiescence. Therefore, suppres￾sion of somatic differentiation through transcriptional regulation might be an evolutionarily conserved theme for germ-cell specification. However, as RNAPII is clearly active in nascent PGCs in mice, the molecules and mechanisms that regulate the process might differ between species. Nature Reviews | Genetics Transposon repression Germ-cell specification Suppression of somatic genes E3.5 E6.0 E7.25 E10.5 E12.5 Meiosis Sperm cell Fully grown oocyte MII oocyte/egg Zygote PGC precursors PGC founder population Migration Repression and activation of germ-cell-specific genes Imprint erasure PGCs settled in gonad Sex differentiation X-chromosome reactivation E13.5 E17.5 Birth/prepuberty/adult Onset of meiosis Maternal imprinting Genome-wide deacetylation Spermatocyte E13.5 Birth/prepuberty/adult Paternal imprinting Control of meiosis MSCI Histone– protamine exchange Spermatogonium PGCs Oocyte growth Maturation Ovulation Genome-wide reprogramming Non-growing oocyte Prospermatogonium Figure 1 | Germ cell development and associated epigenetic events in mice. Chronology of mouse germ cell development and the main epigenetic events that occur. PGCs (primordial germ cells) first emerge at embryonic day 7.25 (E7.25) as a cluster of about 20 cells. Subsequently, they rapidly proliferate with an average doubling time of approximately 16 hours. Before they stop dividing at E13.5, their number reaches up to about 26,000. MSCI, meiotic sex-chromosome inactivation. R E V I E W S 130 | february 2008 | volume 9 www.nature.com/reviews/genetics © 2008 Nature Publishing Group