REVIEWS Table 1 Impaired meiosis caused by defects in epigenetic modifiers Gene Function Mutant phenotype Suv39h1 and H3K9 trimethyltransfera Male) Arrest at mid to late hromosome synapsis: impaired modification of pericentric heterochromatin H3K9 m (Male and female) Arrest at early pachytene and apoptosis: impaired chromosome dimethyitransferase sis: deregulation of target genes H3K4 trimethyltransfera nd female)Arrest at early pachytene and apoptosis: impaired chromo psis and recombination; impaired activation of meiosis-specific genes Dnmt3a De novo DNA methyltransferase ( Male) Arrest at pachytene and apoptosis; imprinting failure 52 Dnmt3L Regulator of DNA methylation (Male) Arrest at pachytene and apoptosis: impaired chromosome synapsis; 53,54.68 imprinting failure; derepression of retrotransposons Chromatin remodelling protein (Female)Arrest and apoptosis at diplotene; impaired chromosome synapsis and of SNF2-helicase family Sami Polycomb group protein (Male)Apoptosis at late pachytene; abnormal chromatin modifications at XY body 86 Piwi family protein; small RNA (Male) Arrest at early pachytene and apoptosis; derepression of retrotransposon ulation Dnmt3a, DNA methyltransferase 3a: Ehmt2, euchromatic histone-lysine N-methyltransferase 2, also known as G9a: Lsh, lymphoid-specific helicase: Prdm9, PR domain-containing 9, also known as Meisetz: Scmhl, sex comb on midleg homologue 1. depends on the function of BRCAl, and that yH2AX that autosomal transgenes carrying an X-inactivation localizes on sex chromosomes in an ATR-dependent centre do not undergo MSCI but can induce imprinted inactivation of the inserted region". Furthermore, it wa The XY body shows characteristic changes in histone shown that the paternal X chromosome is transcribed modifications including deacetylation of histones H3 at zygotic gene activation in female embryos, arguing and H4 and dimethylation of H3K9 during pachytene, against the pre-inactivation modelo. Therefore, the rela consistent with the inactive state. Also, H3K4me2 tionship between MSCI and imprinted X inactivation is and H3K4me3 are over- and under-represented, yet to be clarified. respectively. Interestingly, loss of function of PRDM9 causes a failure of XY-body formation. This sug- Histone deacetylation in maturating oocytes and segre gests that PRDM9 might methylate autosomal loci gation of meiotic chromosomes. In mouse oocytes, his- hat are crucial for XY-body formation to keep them tones H3 and H4 are generally acetylated at prophase I transcriptionally active. of meiosis, but they rapidly become deacetylated at SCMHI(sex comb on midleg homologue 1), which is metaphase I (MI) by histone deacetylases(HDACs) component of Polycomb repressive complex 1(PRC1)(FIG 4). In vitro culture of germinal-vesicle-stage oocytes is involved in histone modifications of the XY body that have been arrested at prophase I in the presence and progression of meiotic prophase 6. In cells that lack of trichostatin A, an inhibitor of HDACs, showed functional SCMHl, meiosis arrests at late pachytene. that neither meiotic maturation, fertilization nor pre Ra normal spermatocytes, PRCl components as well implantation development is affected%2.However,a as H3K27me3 are excluded from the XY body at late closer examination revealed that chromosomes are not pachytene, whereas they are abnormally retained on the properly aligned at the metaphase plate in MIl oocytes, XY body in Scmhl-mutant spermatocytes A failure of and that aneuploidy is frequent in single-cell zygotes H3K9me and H3K9me2 accumulation in the XY body Consequently, about half of embryos derived from the and a failure of phosphorylated RNAPII exclusion were trichostatin-A-treated oocytes died in utero Importanth also observed in the mutants. Therefore, SCMHI is histones remained acetylated in the oocytes of older the xY body ho,. c changes in histone modification in (10-month old)female mice, suggesting that the high modifications, the inactivation of XY chromosomes is in older pregnancies might be due to inadequate histone not affected by the Scmhl mutation, and it is currently deacetylation. Histone deacetylation might be involved sted in specific chromosomal structure that is important fo It has been suggested that MSCI might have a role chromosome segregation. imprinted X-chromosome inactivation. A model has been proposed in which imprinted X inactivation results Epigenetic changes during gamete maturation from inheritance of an X chromosome that has been After meiosis, both male and female germ cells undergo Aneuploidy pre-inactivated by MSCI from the paternal germline?. final developmental changes, at the level of both their esence of an abnormal number of chromosome This model is supported by the observation that the morphology he epigenome, to allow them to carry X chromosome is persistently repressed in postmeiotic out their roles in fertilization and the initial stages of of trisomies, an extra copy of haploid cells and retains repressive modifications such as zygotic development In haploid round spermatids, glo- H3K9me2 (REFS 88, 89). However, other studies showed bal nuclear remodelling occurs, although some histone @2008 Nature Publishing GroupAneuploidy Presence of an abnormal number of chromosomes. For example, in the case of trisomies, an extra copy of a chromosome is present. depends on the function of BRCA1, and that γH2AX localizes on sex chromosomes in an ATR-dependent manner84. The XY body shows characteristic changes in histone modifications including deacetylation of histones H3 and H4 and dimethylation of H3K9 during pachytene, consistent with the inactive state85. Also, H3K4me2 and H3K4me3 are over- and under-represented, respectively. Interestingly, loss of function of PRDM9 causes a failure of XY-body formation81. This sug￾gests that PRDM9 might methylate autosomal loci that are crucial for XY-body formation to keep them transcriptionally active. SCMH1 (sex comb on midleg homologue 1), which is a component of Polycomb repressive complex 1 (PRC1) is involved in histone modifications of the XY body and progression of meiotic prophase86. In cells that lack functional SCMH1, meiosis arrests at late pachytene86. In normal spermatocytes, PRC1 components as well as H3K27me3 are excluded from the XY body at late pachytene, whereas they are abnormally retained on the XY body in Scmh1-mutant spermatocytes. A failure of H3K9me and H3K9me2 accumulation in the XY body and a failure of phosphorylated RNAPII exclusion were also observed in the mutants. Therefore, SCMH1 is required for specific changes in histone modification in the XY body. However, in spite of the aberrant histone modifications, the inactivation of XY chromosomes is not affected by the Scmh1 mutation, and it is currently unclear why meiosis is arrested86. It has been suggested that MSCI might have a role in imprinted X-chromosome inactivation. A model has been proposed in which imprinted X inactivation results from inheritance of an X chromosome that has been pre-inactivated by MSCI from the paternal germline87. This model is supported by the observation that the X chromosome is persistently repressed in postmeiotic haploid cells and retains repressive modifications such as H3K9me2 (REFS 88,89). However, other studies showed that autosomal transgenes carrying an X-inactivation centre do not undergo MSCI but can induce imprinted inactivation of the inserted region90. Furthermore, it was shown that the paternal X chromosome is transcribed at zygotic gene activation in female embryos, arguing against the pre-inactivation model90. Therefore, the rela￾tionship between MSCI and imprinted X inactivation is yet to be clarified. Histone deacetylation in maturating oocytes and segre￾gation of meiotic chromosomes. In mouse oocytes, his￾tones H3 and H4 are generally acetylated at prophase I of meiosis, but they rapidly become deacetylated at metaphase I (MI) by histone deacetylases (HDACs)91 (FIG. 4). In vitro culture of germinal-vesicle-stage oocytes that have been arrested at prophase I in the presence of trichostatin A, an inhibitor of HDACs, showed that neither meiotic maturation, fertilization nor pre￾implantation development is affected92. However, a closer examination revealed that chromosomes are not properly aligned at the metaphase plate in MII oocytes, and that aneuploidy is frequent in single-cell zygotes. Consequently, about half of embryos derived from the trichostatin-A-treated oocytes died in utero. Importantly, histones remained acetylated in the oocytes of older (10-month old) female mice, suggesting that the high incidence of aneuploidy (such as trisomy 21 in humans) in older pregnancies might be due to inadequate histone deacetylation. Histone deacetylation might be involved in specific chromosomal structure that is important for chromosome segregation. Epigenetic changes during gamete maturation After meiosis, both male and female germ cells undergo final developmental changes, at the level of both their morphology and the epigenome, to allow them to carry out their roles in fertilization and the initial stages of zygotic development. In haploid round spermatids, glo￾bal nuclear remodelling occurs, although some histone Table 1 | Impaired meiosis caused by defects in epigenetic modifiers Gene Function of protein Mutant phenotype Refs Suv39h1 and Suv39h2 H3K9 trimethyltransferase (Male) Arrest at mid to late pachytene and apoptosis in double mutants; impaired chromosome synapsis; impaired modification of pericentric heterochromatin 79 Ehmt2 H3K9 mono- and dimethyltransferase (Male and female) Arrest at early pachytene and apoptosis; impaired chromosome synapsis; deregulation of target genes 80 Prdm9 H3K4 trimethyltransferase (Male and female) Arrest at early pachytene and apoptosis; impaired chromosome synapsis and recombination; impaired activation of meiosis-specific genes; impaired XY body formation 81 Dnmt3a De novo DNA methyltransferase (Male) Arrest at pachytene and apoptosis; imprinting failure 52 Dnmt3L Regulator of DNA methylation (Male) Arrest at pachytene and apoptosis; impaired chromosome synapsis; imprinting failure; derepression of retrotransposons 53, 54, 68 Lsh Chromatin remodelling protein of SNF2-helicase family (Female) Arrest and apoptosis at diplotene; impaired chromosome synapsis and recombination; demethylation of retrotransposons and tandem repeats 76 Scmh1 Polycomb group protein (Male) Apoptosis at late pachytene; abnormal chromatin modifications at XY body 86 Mili Piwi family protein; small RNA regulation (Male) Arrest at early pachytene and apoptosis; derepression of retrotransposons 70, 71 Dnmt3a, DNA methyltransferase 3a; Ehmt2, euchromatic histone-lysine N-methyltransferase 2, also known as G9a; Lsh, lymphoid-specific helicase; Prdm9, PR domain-containing 9, also known as Meisetz; Scmh1, sex comb on midleg homologue 1. R E V I E W S 136 | february 2008 | volume 9 www.nature.com/reviews/genetics © 2008 Nature Publishing Group