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- and genomic integrity. Understanding epigenetic regulation in germ cells har of meiosis expression programme that is required for germ-cell development, regulation 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 genotype. In molecular terms, it repre- differentiation, cells start in a pluripotent state and make a nts 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 types. Their gene-expression programme 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 Organization of Information parental cell development that are relevant to these epigenetic events 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-. 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 niversity for Advanced udies, 1111 yata germ cells are unique in that they can give rise to a new maintaining genomic integrity in these cells 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 a zygote, which is totipotent- it can develop a whole opment. Recent studies have identified a number of epi stitute of Development, new organism. For the zygote to acquire this totipo- genetic modifiers, including DNA methyltransferase ging and Cancer, Tohoku niversity, Seiryo-machi4-I, tency, germ cells and the zygote undergo extensive ep histone-modification enzymes and their regulatory genetic reprogramming. In mammalian germ cells, factors, that have crucial influences on germ-cell devel Correspondence to HSor Y.M. reprogramming also strips existing parental imprints opment. There is also an increasing understanding of epigenetic marks that ensure parental-origin- the mechanisms of the epigenetic reprogramming that hisasakiglab nig acip: pecific monoallelic expression of about a hundred takes place during germ-cell development-for exam do:10.1038/nrg229 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 and female gametes progression of events during germ-cell development, NATURE REVIEWS GENETICS VOLUME 9 FEBRUARY 2008 129 @2008 Nature Publishing GroupEpigenetics refers to a collection of mechanisms and phenomena that define the phenotype of a cell without affecting the genotype1 . In molecular terms, it repre￾sents a range of chromatin modifications including DNA methylation, histone modifications, remodelling of nucleosomes and higher order chromatin reorganiza￾tion. These epigenetic modifications constitute a unique profile in each cell and define cellular identity by regulating gene expression. Epigenetic profiles are modifiable during cellular differentiation, but herit￾ability is an important aspect of epigenetics: it ensures that daughter cells have the same phenotype as the parental cell. The process of germ-cell development is regulated by both genetic and epigenetic mechanisms2–5. Among the various cell types that constitute an animal body, germ cells are unique in that they can give rise to a new organism. On fertilization, the products of germ-cell development, the oocyte and sperm cell, fuse to form a zygote, which is totipotent — it can develop a whole new organism2 . For the zygote to acquire this totipo￾tency, germ cells and the zygote undergo extensive epi￾genetic reprogramming2,3. In mammalian germ cells, reprogramming also strips existing parental imprints — epigenetic marks that ensure parental-origin￾specific monoallelic expression of about a hundred mammalian imprinted genes in the next generation — and establishes new ones that are different in male and female gametes. The role of epigenetics in germ cells can be viewed differently from that in somatic cells. During somatic cell differentiation, cells start in a pluripotent state and make a series of decisions about their fates, thereby giving rise to a range of cell types6 . Their gene-expression programmes become more restricted and potentially locked in by changes in epigenetic modifications. However, germ cells are different in that, once their fate has been determined during early development, there is no need for develop￾mental decisions to be made. Instead, germ cells have a specific fate and go through a series of epigenetic events that are unique to this cell type. The aspects of germ-cell development that are relevant to these epigenetic events are the need for a unique gene-expression programme that is different from somatic cells, the fact that germ cells undergo meiosis and the particular importance of maintaining genomic integrity in these cells. In this Review, we discuss dynamic epigenetic changes that occur during mammalian germ-cell devel￾opment. Recent studies have identified a number of epi￾genetic modifiers, including DNA methyltransferases, histone-modification enzymes and their regulatory factors, that have crucial influences on germ-cell devel￾opment. There is also an increasing understanding of the mechanisms of the epigenetic reprogramming that takes place during germ-cell development — for exam￾ple, how imprints are re-established in the male and female germ cells. Our discussion follows the temporal progression of events during germ-cell development, *Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems & Department of Genetics, School of Life Science, The Graduate University for Advanced Studies, 1111 Yata, Mishima 411‑8540, Japan. ‡Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4‑1, Sendai 980‑8575, Japan. Correspondence to H.S. or Y.M. e-mails: hisasaki@lab.nig.ac.jp; ymatsui@idac.tohoku.ac.jp doi:10.1038/nrg2295 Published online 16 January 2008 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. R E V I E W S nature reviews | genetics volume 9 | february 2008 | 129 © 2008 Nature Publishing Group