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Epigenetic Events in Mammalian Germ-Cell Development: Reprogramming and Beyond

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Epigenetic Events in Mammalian Germ-Cell Development: Reprogramming and Beyond REVIEWS Epigenetic events in mammalian germ-cell development: reprogramming and beyond Hiroyuki Sasaki* and Yasuhisa Matsui‡ Abstract | The epigenetic profile of germ cells, which is defined by modifications of DNA and chromatin, changes dynamically during their development. Many of the changes are associated with the acquisition of the capacity to support post-fertilization development. Our knowledge of this aspect has greatly increased— for example, insights into how the re-establishment of parental imprints is regulated. In addition, an emerging theme from recent studies is that epigenetic modifiers have key roles in germ-cell development itself — for example, epigenetics contributes to the gene- expression programme that is required for germ-cell development, regulation of meiosis and genomic integrity. Understanding epigenetic regulation in germ cells has implications for reproductive engineering technologies and human health. Epigenetics refers to a collection of mechanisms and The role of epigenetics in germ cells can be viewed phenomena that define the phenotype of a cell without differently from that in somatic cells. During somatic cell affecting the genotype1. In molecular terms, it repre- differentiation, cells start in a pluripotent state and make a sents a range of chromatin modifications including series of decisions about their fates, thereby giving rise to DNA methylation, histone modifications, remodelling of a range of cell types6. Their gene-expression programmes nucleosomes and higher order chromatin reorganiza- become more restricted and potentially locked in by tion. These epigenetic modifications constitute a changes in epigenetic modifications. However, germ cells unique profile in each cell and define cellular identity are different in that, once their fate has been determined by regulating gene expression. Epigenetic profiles are during early development, there is no need for develop- *Division of Human Genetics, modifiable during cellular differentiation, but herit- mental decisions to be made. Instead, germ cells have a Department of Integrated ability is an important aspect of epigenetics: it ensures specific fate and go through a series of epigenetic events Genetics, National Institute that daughter cells have the same phenotype as the that are unique to this cell type. The aspects of germ-cell of Genetics, Research Organization of Information parental cell. development that are relevant to these epigenetic events and Systems & Department The process of germ-cell development is regulated are the need for a unique gene-expression programme of Genetics, School of Life by both genetic and epigenetic mechanisms2–5. Among that is different from somatic cells, the fact that germ Science, The Graduate the various cell types that constitute an animal body, cells undergo meiosis and the particular importance of University for Advanced germ cells are unique in that they can give rise to a new maintaining genomic integrity in these cells. Studies, 1111 Yata, Mishima 411-8540, Japan. organism. On fertilization, the products of germ-cell In this Review, we discuss dynamic epigenetic ‡Cell Resource Center for development, the oocyte and sperm cell, fuse to form changes that occur during mammalian germ-cell devel- Biomedical Research, a zygote, which is totipotent — it can develop a whole opment. Recent studies have identified a number of epi- Institute of Development, new organism2. For the zygote to acquire this totipo- genetic modifiers, including DNA methyltransferases, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, tency, germ cells and the zygote undergo extensive epi- histone-modification enzymes and their regulatory 2,3 Sendai 980-8575, Japan. genetic reprogramming . In mammalian germ cells, factors, that have crucial influences on germ-cell devel- Correspondence to H.S. or Y.M. reprogramming also strips existing parental imprints opment. There is also an increasing understanding of e-mails: — epigenetic marks that ensure parental-origin- the mechanisms of the epigenetic reprogramming that [email protected]; specific monoallelic expression of about a hundred takes place during germ-cell development — for exam- [email protected] doi:10.1038/nrg2295 mammalian imprinted genes in the next generation ple, how imprints are re-established in the male and Published online — and establishes new ones that are different in male female germ cells. Our discussion follows the temporal 16 January 2008 and female gametes. progression of events during germ-cell development, natUre reVieWS | GENETICS VOLUME 9 | feBRUarY 2008 | 129 © 2008 Nature Publishing Group REVIEWS Paternal Control of meiosis Histone– imprinting protamine MSCI exchange Birth/prepuberty/adult Germ-cell specification E13.5 Repression and activation of germ-cell-specific genes Suppression of somatic genes Transposon repression Meiosis Sperm cell PGC founder Spermatocyte PGC population precursors Spermatogonium Prospermatogonium Zygote PGCs Non-growing oocyte MII oocyte/egg Migration PGCs settled in gonad Onset of Sex differentiation meiosis Fully grown oocyte Oocyte Maturation growth E3.5 E6.0 E7.25 E10.5 E12.5 Ovulation Genome-wide Imprint erasure reprogramming E13.5 E17.5 Birth/prepuberty/adult X-chromosome reactivation Maternal Genome-wide imprinting deacetylation 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 averageNa doublingture Revie timews | ofGenetics approximately 16 hours. Before they stop dividing at E13.5, their number reaches up to about 26,000. MSCI, meiotic sex-chromosome inactivation. DNA methylation A covalent modification that occurs predominantly at CpG and we describe the epigenetic changes and their might be important for this suppression. PGC-like cells dinucelotides in the vertebrate contributions to germ-cell-specific functions at each in Blimp1-null embryos have aberrant expression of the genome. It is catalysed by stage. Understanding the epigenetic changes that take Hox genes16, which are normally repressed in PGCs. This DNA methyltransferases place during germ-cell development has important suggests that BLIMP1 is crucial for suppression of the and converts cytosines to implications for animal cloning, assisted reproductive somatic programme, which might ensure that the PGC 5-methylcytosines. It represses transcription directly by technologies and human health. precursors and nascent PGCs are restricted to the germ- inhibiting the binding of cell fate. In organisms such as Caenorhabditis elegans specific transcription factors, Germ-cell specification and differentiation and Drosophila melanogaster, this repression involves and indirectly by recruiting Determination and maintenance of the germ-cell fate. global inhibition of RNA polymerase II (RNAPII)- methyl-CpG-binding proteins 17–19 and their associated repressive In post-implantation mammalian embryos, a popula- dependent transcription . In D. melanogaster, the chromatin-remodelling tion of pluripotent cells in the epiblast gives rise to pri- pole cells that develop into PGCs also have reduced activities. mordial 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 Histones undergo post- primitive streak translational modifications the posterior end of the 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- with DNA and nuclear Before the final specification of PGCs, their precursors gramme20. Here, maternally inherited molecules such proteins. In particular, the tails are induced within the proximal epiblast cell popula- as the products of gcl (germ-cell-less)21,22, pgc (polar of histones H3 and H4 can be 23,24 20,25 covalently modified at several tion by signals from the adjacent extra-embryonic ecto- granule component) and nanos are involved in 10–15 residues. Modifications of derm . A transcriptional regulator, B‑lymphocyte the transcriptional quiescence. Therefore, suppres- the tail include methylation, maturation-induced protein 1 (BLIMP1, also known as sion of somatic differentiation through transcriptional acetylation, phosphorylation PR-domain-containing 1), is expressed specifically in regulation might be an evolutionarily conserved theme and ubiquitylation, and the precursor cells as early as E6.25 (REF. 16), and this for germ-cell specification. However, as RNAPII is influence several biological processes, including gene molecule is essential for PGC specification. clearly active in nascent PGCs in mice, the molecules expression, DNA repair and The PGC precursors need to suppress the somatic gene- and mechanisms that regulate the process might differ chromosome condensation. expression programme, and epigenetic modifications between species. 130 | feBRUarY 2008 | VOLUME 9 www.nature.com/reviews/genetics © 2008 Nature Publishing Group REVIEWS 5meC The global changes in repressive marks in migrat- H3K9me1/2 ing PGCs might reflect the reprogramming
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