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Epigenetic events in mammalian germ-cell development: reprogramming and beyond

Nature Reviews Genetics volume 9, pages 129–140 (2008)Cite this article

Key Points

  • Accumulating evidence indicates that epigenetic modifiers have key roles in genome-wide reprogramming and activation and repression of specific genes during mammalian germ-cell development.

  • Germ-cell specification and suppression of the somatic gene expression programme might involve epigenetic modifications. Furthermore, differentiating primordial germ cells (PGCs) show global reduction in repressive epigenetic marks, and activation and repression of post-migratory PGC-specific genes involves DNA methylation and histone-arginine methylation.

  • In post-migratory PGCs, epigenetic imprints that are specific to the parent of origin are erased. Subsequently, sex-specific imprints are established during male and female gametogenesis, and the de novo DNA methylation machinery has a central role in this process.

  • DNA methylation is important for silencing retrotransposons in germ cells and therefore contributes to the maintenance of genomic integrity. Recent studies have revealed a link between DNA methylation and small-RNA-mediated silencing mechanisms.

  • A number of histone methyltransferases are essential for establishing a chromosome structure that is appropriate for events that occur during meiosis and for activation and repression of genes that are necessary or unnecessary for meiosis. Meiotic sex-chromosome inactivation in male germ cells involves histone variants and epigenetic modifications.

  • Global nuclear remodelling including histone–protamine exchange occurs in haploid spermatids. Expression of some haploid-specific genes relies on histone demethylation.

  • A better understanding of the epigenetic regulation of germ-cell development will be of great importance for improvement of reproductive engineering technologies and human health.

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.

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Figure 1: Germ cell development and associated epigenetic events in mice.
Figure 2: Epigenetic reprogramming in primordial germ cells (PGCs).
Figure 3: Cross-talk between DNA methylation, histone marks and the piRNA pathway in male germ cells.
Figure 4: Epigenetic changes that occur during meiosis in male and female gametogenesis.

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Acknowledgements

We are grateful to S. Tomizawa, T. Horiike and K. Takada for their help in preparation of the manuscript. Research in our laboratories is supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and Ministry of Education, Culture, Sports, Science and Technology of Japan.

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  1. Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Sendai 980-8575, Japan.

Authors and Affiliations

  1. Division of Human Genetics, Department of Integrated Genetics, Research Organization of Information and Systems & Department of Genetics, National Institute of Genetics, School of Life Science, The Graduate University for Advanced Studies, 1111 Yata, Mishima, 411-8540, Japan

    Hiroyuki Sasaki & Yasuhisa Matsui

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  1. Hiroyuki Sasaki
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  2. Yasuhisa Matsui
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Correspondence to Hiroyuki Sasaki or Yasuhisa Matsui.

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Glossary

DNA 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.

Nucleosome

The basic structural subunit of chromatin, responsible in part for the compactness of a chromosome. Each nucleosome consists of a sequence of DNA wrapped around a histone core, which is a histone octamer containing two copies of each of the core histones: H2A, H2B, H3 and H4.

Pluripotent

Able to give rise to a wide range of, but not all, cell lineages (usually all fetal lineages and a subset of extraembryonic lineages).

Epiblast

An embryonic lineage that is derived from the inner cell mass of the blastocyst, which gives rise to the body of the fetus.

Gastrulation

A process of cell and tissue movements whereby the cells of the blastula are rearranged to form a three-layered body plan, which consists of the outer ectoderm, inner ectoderm and interstitial mesoderm.

Primitive streak

A transitory embryonic structure, which is present as a strip of cells, that pre-figures the anterior–posterior axis of the embryo. During gastrulation embryonic cells progress through the streak.

Embryonic stem cell

A type of pluripotent stem cell that is derived from the inner cell mass of the early embryo. Pluripotent cells are capable of generating virtually all cell types of the organism.

Blastocyst

An early stage of mammalian embryonic development at which the first cell lineages become established.

Embryoid body

Spherical structure formed by differentiating ES cells in culture, which resembles the early embryo.

X-chromosome inactivation

The process that occurs in female mammals by which gene expression from one of the pair of X chromosomes is downregulated to match the levels of gene expression from the single X chromosome that is present in males. The inactivation process involves a range of epigenetic mechanisms on the inactivated chromosome, including changes in DNA methylation and histone modifications.

Chromosome synapsis

The association or pairing of the two pairs of sister chromatids (representing homologous chromosomes) that occurs at the start of meiosis.

Argonaute proteins

Argonaute proteins are the central components of RNA-silencing mechanisms. They provide the platform for target-mRNA recognition by short guide RNA strands and the catalytic activity for mRNA cleavage.

Pericentric heterochromatin

This is the highly compacted chromatin region that is juxtaposed to centromeres and contains large blocks of tandem repeats. It is irreversibly silenced and remains so throughout the cell cycle.

Histone variants

Structurally distinct, non-typical versions of the histone proteins. They are encoded by independent genes and often subject to regulation that is distinct from that of the canonical histones.

Aneuploidy

Presence of an abnormal number of chromosomes. For example, in the case of trisomies, an extra copy of a chromosome is present.

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Sasaki, H., Matsui, Y. Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat Rev Genet 9, 129–140 (2008). https://doi.org/10.1038/nrg2295

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