REVIEWS Primary spermatocyte Diakinesis I H3K9mel 2 H3K9me3 1111111111111111111111 H3K27me3 a!I1 H3ac/H4ac protamin XY body Primary oocyte econdary oocyte Leptotene Pachytene oocyte/egg Growth Extrusion of first Maternal imprinting Figure 4 Epigenetic changes that occur during meiosis in male and female gametogenesis. Changes in epigenetic modifications that occur at various stages of meiosis in male and female germ-cell development are shown. Dashed lines indicate that the level of epigenetic modification is lower during these periods than that during the periods shown by the solid lines. FG. fully grown; MSCI, meiotic sex-chromosome inactivation: ML, metaphase l MIl, metaphase lI; NG, non-growing: PGC, primordial germ celL. marks such as H3K9me2 on the inactive X chromosome chromatin retains up to 15% of the spermatid histones, are retained. A testis-specific linker histone variant and some regions- such as the human protamine gene HIT2 appears at this stage and has an important role cluster and imprinted IG F2 (insulin-like growth factor 2) in chromatin condensation during spermiogenesis 3. -have been reported to be histone-rich. The presence Later, another linker histone variant HILSI(histone-l- of somatic-like chromatin in the sperm nucleus could like protein in spermatids 1)appears in elongated sper- provide a means to transmit epigenetic information matids. In the process of histone-protamine exchange, to the offspring histones are first replaced by TNPI(transition protein 1) The genome-wide DNA methylation pattern changes and TNP2 and then by protamines, and phosphoryla- little during spermiogenesis, as its acquisition has been tion and dephosphorylation of these proteins regulate completed by the end of the pachytene spermatocyte the process. Very recently, the JmjC-domain-contain- stage. However, there is evidence that specific loci such ng histone demethylase 2A(IHDM2A, also known as as Pak2 (phosphoglycerate kinase 2)become de novo JMJD1A), which is an H3K9me1/2-specific demethylase, methylated as late as the sperm-maturation period in the was shown to be necessary for the specific activation of epididymis, the mechanism of which is unknown. As InpI and PrmI (protamine 1). The incorporation of Pgk2 is only expressed in spermatocytes and spermatids, protamines into sperm chromatin induces DNA compac- this methylation might preclude unnecessary activation tion, which is necessary for the formation of spermatozoa of this f and for providing a safe environment for the genome, A recent report showed that there are numerous resistant to physical damage and chemical agents. intra-and inter-individual differences in DNA methyla However, an interesting twist is that mammalian sperm tion in human sperm samples", which could contribute NATURE REVIEWS GENETICS @2008 Nature Publishing Groupmarks such as H3K9me2 on the inactive X chromosome are retained88,89. A testis-specific linker histone variant H1T2 appears at this stage and has an important role in chromatin condensation during spermiogenesis93. Later, another linker histone variant HILS1 (histone-1- like protein in spermatids 1) appears in elongated sper￾matids. In the process of histone–protamine exchange, histones are first replaced by TNP1 (transition protein 1) and TNP2 and then by protamines5,94, and phosphoryla￾tion and dephosphorylation of these proteins regulate the process5 . Very recently, the JmjC-domain-contain￾ing histone demethylase 2A (JHDM2A, also known as JMJD1A), which is an H3K9me1/2-specific demethylase, was shown to be necessary for the specific activation of Tnp1 and Prm1 (protamine 1)95. The incorporation of protamines into sperm chromatin induces DNA compac￾tion, which is necessary for the formation of spermatozoa and for providing a safe environment for the genome, resistant to physical damage and chemical agents. However, an interesting twist is that mammalian sperm chromatin retains up to 15% of the spermatid histones, and some regions — such as the human protamine gene cluster and imprinted IGF2 (insulin-like growth factor 2) — have been reported to be histone-rich96. The presence of somatic-like chromatin in the sperm nucleus could provide a means to transmit epigenetic information to the offspring. The genome-wide DNA methylation pattern changes little during spermiogenesis, as its acquisition has been completed by the end of the pachytene spermatocyte stage97. However, there is evidence that specific loci such as Pgk2 (phosphoglycerate kinase 2) become de novo methylated as late as the sperm-maturation period in the epididymis98, the mechanism of which is unknown. As Pgk2 is only expressed in spermatocytes and spermatids, this methylation might preclude unnecessary activation of this gene during post-fertilization development. A recent report showed that there are numerous intra- and inter-individual differences in DNA methyla￾tion in human sperm samples99, which could contribute Secondary spermatocyte Spermatid Spermatozoan (sperm cell) Spermatogonium Leptotene Zygotene Pachytene Diplotene Synapsis Recombination Extrusion of first polar body Ovulation Maturation Resumption of meiosis MSCI XY body Histone– protamine exchange Diakinesis MI MII Leptotene Zygotene Pachytene Diplotene MI PGC Secondary oocyte (FG oocyte) (MII oocyte/egg) Synapsis Recombination Growth (NG oocyte) Maternal imprinting Nature Reviews | Genetics H3K9me1/2 H3ac/H4ac H3K9me3 H3K27me3 Primary spermatocyte Primary oocyte H3K9me1/2 H3K9me3 H3ac/H4ac Entry into meiosis Entry into meiosis Figure 4 | Epigenetic changes that occur during meiosis in male and female gametogenesis. Changes in epigenetic modifications that occur at various stages of meiosis in male and female germ-cell development are shown. Dashed lines indicate that the level of epigenetic modification is lower during these periods than that during the periods shown by the solid lines. FG, fully grown; MSCI, meiotic sex-chromosome inactivation; MI, metaphase I; MII, metaphase II; NG, non-growing; PGC, primordial germ cell. R E V I E W S nature reviews | genetics volume 9 | february 2008 | 137 © 2008 Nature Publishing Group