NATUREIVol 447 24 May 2007 INSIGHT REVIEW cancer. Consequently, these genes are difficult to reactivate in cloned this involves demethylation of DNA PGCs at these stages have similar embryos because of inefficient reprogramming of repressive marks, par- properties to pluripotent cells, including the ability to form embryonic ularly of DNA methylation germ cells in culture". These studies are important because they are c Special epigenetic regulation needs to occur in PGCs developing in the first to show that in some developmental situations, removal of the early post-implantation embryo. Because these cells emerge from epigenetic marks( H3K27 methylation in the ES-cell study, and DNA ell types in the egg cylinder that are already on the way to lineage com- methylation in the PGC study) could be crucial for the activation of mitment and differentiation, the somatic gene-expression programme developmental genes. Whether DNA methylation in PGCs is erased needs to be suppressed. One of the key regulators of this process is by an active or a passive mechanism is unclear(discussed later). The BLIMPI(B-lymphocyte-induced maturation protein 1), which associ- promoters of the genes that undergo developmental demethylation tes with the arginine methyltransferase PRMT5 PRMT5 might partly (for example, Mvh, Dazl and Sycp3)contain CpG islands, as do the dif- repress Hox-family genes and other somatic genes in PGCs(Fig. 2c). ferentially methylated regions(DMRs)of imprinted genes, which als Pluripotency-associated genes and genes that have later roles in germ- undergo demethylation at these stages of PGC development. I am not cell development can also be repressed by DNA methylation(Fig 2b). aware of any reports of demethylation of CpG islands during develop So genes such as Mwh(also known as Ddx4), Dazl( deleted in azoo- ment other than in PGCs or in the zygote and pre- implantation embryo permia-like)and Sycp3(synaptonemal complex protein 3)are meth-(discussed later). Methylation of CpG islands might only be removable ylated in early PGCs and begin to be expressed after the erasure of DNA under exceptional circumstances. methylation which occurs between embryonic day(E)8.0 and E12.5 Some key pluripotency-associated genes(such as Oct4 and Nanog) in PGCs. Interestingly, pluripotency-associated genes such as Nanog are epigenetically inactivated at later stages of gametogenesis and in also begin to be reactivated at these stages, but it is not known whether the mature gametes, including by DNA methylation. Therefore, after Temporary repression of developmental genes by the peG protein system Histone demethylase? Repression of pluripotency-associated genes by histone methylation and dNA methylation Pluripotent Differentiated c Maintenance of silencing of somatic genes in early germ cells rly PGC Histone demethylase? Histone methyltransferase tion of b, Pluripotency-associated genes are stably silenced during genes during the differentiation of somatic cells and differentiation, through histone methylation and DNA methylation germ cells. The expression or repr h as oct and d developmental genes is indicated, and the associated modifications ES-cell differentiation, and this process can involve both histone of the histone tails and/or DNA are represented by different colours. methylation(such as methylation of H3k9 mediated by G9A; also a, In pluripotent cells, the repression of genes that are needed later in known as EHMT2)(green) and DNA methylation(red). Whethera development is flexible and can involve the PcG-protein repressive histone demethylase is required for the removal of H3K4 methylation system. Silent developmental genes an be marked by both H3K27 is unknown. c, For germ-cell development, the repression of somatic methylation (yellow)and H3K4 methylation(blue), possibly allowing genes needs to be maintained in early germ cells, and this process might rapid gene activation after loss of repression by PcG-protein-containi involve histone arginine methylation(pink). Hox-family genes and other developmental genes remain silent in early germ cells; some of this involves a histone demethylase is unknown. Further increases in H3K4 silencing might require histone arginine methylation brought about by methylation might be required for proper developmental gene expression. PRMT5 27 @2007 Nature Publishing Groupcancer16. Consequently, these genes are difficult to reactivate in cloned embryos because of inefficient reprogramming of repressive marks, par￾ticularly of DNA methylation17. Special epigenetic regulation needs to occur in PGCs developing in the early post-implantation embryo18. Because these cells emerge from cell types in the egg cylinder that are already on the way to lineage com￾mitment and differentiation, the somatic gene-expression programme needs to be suppressed. One of the key regulators of this process is BLIMP1 (B-lymphocyte-induced maturation protein 1), which associ￾ates with the arginine methyltransferase PRMT5. PRMT5 might partly repress Hox-family genes and other somatic genes in PGCs19 (Fig. 2c). Pluripotency-associated genes and genes that have later roles in germ￾cell development can also be repressed by DNA methylation (Fig. 2b). So genes such as Mvh (also known as Ddx4), Dazl (deleted in azoo￾spermia-like) and Sycp3 (synaptonemal complex protein 3) are meth￾ylated in early PGCs and begin to be expressed after the erasure of DNA methylation20, which occurs between embryonic day (E) 8.0 and E12.5 in PGCs. Interestingly, pluripotency-associated genes such as Nanog also begin to be reactivated at these stages, but it is not known whether this involves demethylation of DNA. PGCs at these stages have similar properties to pluripotent cells, including the ability to form embryonic germ cells in culture21. These studies are important because they are the first to show that in some developmental situations, removal of epigenetic marks (H3K27 methylation in the ES-cell study, and DNA methylation in the PGC study) could be crucial for the activation of developmental genes. Whether DNA methylation in PGCs is erased by an active or a passive mechanism is unclear (discussed later). The promoters of the genes that undergo ‘developmental’ demethylation (for example, Mvh, Dazl and Sycp3) contain CpG islands, as do the dif￾ferentially methylated regions (DMRs) of imprinted genes, which also undergo demethylation at these stages of PGC development. I am not aware of any reports of demethylation of CpG islands during develop￾ment other than in PGCs or in the zygote and pre-implantation embryo (discussed later). Methylation of CpG islands might only be removable under exceptional circumstances. Some key pluripotency-associated genes (such as Oct4 and Nanog) are epigenetically inactivated at later stages of gametogenesis and in the mature gametes, including by DNA methylation. Therefore, after a Temporary repression of developmental genes by the PcG protein system b c Pluripotent cell Histone demethylase? Histone methyltransferase Histone demethylase? Histone methyltransferase DNMT Histone demethylase? Histone methyltransferase Pluripotent cell Pluripotent cell Differentiated cell Repression of pluripotency-associated genes by histone methylation and DNA methylation Maintenance of silencing of somatic genes in early germ cells Differentiated cell Early PGC PRC PRC PRMT5 Figure 2 | Epigenetic regulation of pluripotency-associated genes and developmental genes during the differentiation of somatic cells and germ cells. The expression or repression of pluripotency-associated genes and developmental genes is indicated, and the associated modifications of the histone tails and/or DNA are represented by different colours. a, In pluripotent cells, the repression of genes that are needed later in development is flexible and can involve the PcG-protein repressive system. Silent developmental genes can be marked by both H3K27 methylation (yellow) and H3K4 methylation (blue), possibly allowing rapid gene activation after loss of repression by PcG-protein-containing repressive complexes (PRCs). Whether the loss of H3K27 methylation involves a histone demethylase is unknown. Further increases in H3K4 methylation might be required for proper developmental gene expression. b, Pluripotency-associated genes are stably silenced during differentiation, through histone methylation and DNA methylation. For example, genes such as Oct4 and Nanog are silenced during ES-cell differentiation, and this process can involve both histone methylation (such as methylation of H3K9 mediated by G9A; also known as EHMT2) (green) and DNA methylation (red). Whether a histone demethylase is required for the removal of H3K4 methylation is unknown. c, For germ-cell development, the repression of somatic genes needs to be maintained in early germ cells, and this process might involve histone arginine methylation (pink). Hox-family genes and other developmental genes remain silent in early germ cells; some of this silencing might require histone arginine methylation brought about by PRMT5. 427 NATURE|Vol 447|24 May 2007 INSIGHT REVIEW ￾
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