REPRODUCTIONREVIEW

The histone codes for meiosis

Lina Wang1,2,*, Zhiliang Xu1,3,*, Muhammad Babar Khawar4, Chao Liu1 and Wei Li1 1State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, People’s Republic of China, 2University of Chinese Academy of Sciences, Beijing, People’s Republic of China, 3Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China and 4Department of Zoology, University of the Punjab, Lahore, Pakistan Correspondence should be addressed to W Li or C Liu; Email: [email protected] or [email protected] *(L Wang and Z Xu contributed equally to this work)

Abstract

Meiosis is a specialized process that produces haploid gametes from diploid cells by a single round of DNA replication followed by two successive cell divisions. It contains many special events, such as programmed DNA double-strand break (DSB) formation, homologous recombination, crossover formation and resolution. These events are associated with dynamically regulated chromosomal structures, the dynamic transcriptional regulation and chromatin remodeling are mainly modulated by histone modifications, termed ‘histone codes’. The purpose of this review is to summarize the histone codes that are required for meiosis during spermatogenesis and oogenesis, involving meiosis resumption, meiotic asymmetric division and other cellular processes. We not only systematically review the functional roles of histone codes in meiosis but also discuss future trends and perspectives in this field. Reproduction (2017) 154 R65–R79

Introduction becoming shorter and thicker. During the diplotene stage, the chromosomes start to be decondensed, and the Sexual reproduction is an essential way for higher tetrad structures can be observed clearly. Chromosomes eukaryotes to produce offspring, which aims to keep continue to condense during the diakinesis stage, the genome stable and variable. It is achieved by the nucleolus disappears and chromosomes are evenly production of haploid gametes and the fusion of these distributed in the nucleus (Keeney et al. 1997, Zickler gametes. The gametes contain half of the chromosomal & Kleckner 1999, Borner et al. 2004, Strom et al. 2007, number in somatic cell because they are produced by Lange et al. 2016). a specialized cell division with a single round of DNA Different from most of the other meiotic processes, replication, followed by two successive divisions, meiotic process of the female mammals undergoes known as meiosis. Meiosis occurs in almost all sexually two of phases arrest during oocytes maturation. First, reproducing creatures and is highly conserved from the developing oocytes arrest at diplotene stage with a single-cell eukaryotes, such as yeast, to multicellular germinal vesicle (GV) in their nucleus, and this state is eukaryotes, such as insects, fish, birds and mammals maintained until meiosis resumption at puberty or even (Clancy 1998, Yamamoto et al. 1999, Hawley 2002, later. Meiosis resumption is marked by GV breakdown Smith et al. 2008). In contrast to mitosis, meiosis starts (GVBD), which indicates the completion of prophase I from a long premeiotic DNA replication process, and the transition to meiosis I (MI). After that, the oocytes followed by prophase I. According to the chromosomal will be arrested for the second time at metaphase II (MII), configurations, meiosis prophase I can be divided into which will be activated by the fertilization with sperms leptotene, zygotene, pachytene, diplotene and diakinesis (Downs 1996). stages. At the leptotene stage, when the DNA replication Chromosomes are constituted by nucleosomes, has been completed, chromatin starts to fold and condense which are the fundamental unit of chromatin and are to form the fibrous chromosomes. When entering into the composed of DNA and various histones. Two copies zygotene stage, the chromosomes approximately line up of the four histones (H2A, H2B, H3 and H4) constitute with their homologous chromosomes, which are equal the core particle of the nucleosome by forming an in length and position. Following that is the pachytene octamer, and H1 is a linker histone for packing the stage, in which chromosomes condense further, nucleosome into higher-order structures. Histone tails

© 2017 Society for Reproduction and Fertility DOI: 10.1530/REP-17-0153 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 10/03/2021 12:59:21AM via free access

10.1530/REP-17-0153 R66 L Wang, Z Xu and others

can be substituted by their variants or modified by Table 1 Histone modifications and variants in the meiosis. various modifiers, such as acetylation, ubiquitination, Modifications/variants Function Species/cells types Reference methylation and phosphorylation, to regulate the Acetylation chromatin status (Thompson et al. 2013, Watanabe et al. H3K9ac, H3K18ac, H3K23ac Meiotic cell division Mouse/primary spermatocytes Song et al. (2011) 2013, Hiragami-Hamada et al. 2016, Kadoch et al. H3K9ac Gene transcription Primary spermatocytes Li et al. (2017) 2016), which plays essential roles in DNA replication H3K9ac Meiotic recombination Yeast Yamada et al. (2013) (Franke et al. 2016), gene transcription (Yang et al. 2016), hotspots homologous recombination (Yoon et al. 2016), DSB H3K9ac, H3K14ac, H4K5ac, Open chromatin for the Mouse/oocytes Akiyama et al. (2004), Sarmento et al. repair (Lange et al. 2016) and chromatin stability. These H4K8ac, H4K12ac, gene expression in GV (2004), Kageyama et al. (2007), H4K16ac oocytes Nagashima et al. (2007), Gu et al. (2010) histone variants and post-translational modifications H4K5ac, H4K8ac, H4K12ac Transcription in leptotene Mouse/spermatocytes Shirakata et al. (2014) (PTMs) constitute the so-called ‘histone codes’ (Fig.1; and zygotene Tang et al. 2015, Wolfe et al. 2008). More than 50 H4K8ac Chromatin remodeling in Mouse/oocytes Kim et al. (2003) histone PTMs have been identified, and this number meiosis of oocytes is growing rapidly (Grunstein 1997, Jenuwein & Allis H4K16ac Meiotic recombination Yeast Cavero et al. (2016) checkpoint 2001, Eberharter & Becker 2002, Iizuka & Smith 2003, H4K44ac Facilitates homologous Yeast Hu et al. (2015) Zentner & Henikoff 2013). Histone codes have been recombination found to participate and play important roles in meiosis Methylation (Fig. 2, Table 1 and Box 1, 2, 3 and 4) (Maleki & Keeney H3K4me1/me2/me3 Chromatin reorganization Mouse/spermatocytes Godmann et al. (2007) 2004, Hu et al. 2015, Luense et al. 2016, Xu et al. H3K4me3 Programmed DSB hotspots Yeast/mouse spermatocyte/oocytes Borde et al. (2009), Buard et al. (2009), and meiotic Brick et al. (2012), Acquaviva et al. 2016), and the functions of these histone codes during recombination initiation (2013), Sommermeyer et al. (2013) meiosis will be summarized in the following sections of H3K9me1/me2 Synapsis and genes Mouse/spermatocyte/oocytes Tachibana et al. (2007) this review. transcription H3K9me3 Synapsis and pericentric Mouse/spermatocyte Peters et al. (2001), Kato et al. (2015) The histone codes of H1in meiosis heterochromatin modification Histone H1 is the linker histone in nucleosomes, and H3K27me3 Transcriptional silencing Mouse/spermatocyte Song et al. (2011) it is important for higher-order chromatin formation H3K27me3 Transcription activation Mouse/oocytes Xu et al. (2016) Figure 1 The histone codes. The genetic information is stored in the and compaction (Izzo & Schneider 2016). The H3K36me3 Meiotic recombination Mouse/spermatocytes Powers et al. (2016) nucleus and is divided into different chromosomes. The basic units of H3K79me2 Transcriptional reactivation Mouse/spermatocytes Ontoso et al. (2014) the chromosomes are nucleosomes, which contain double-stranded histone H1 family is heterogeneous, and multiple H3K79me3 Transcription repression on Mouse/spermatocytes Ontoso et al. (2014) DNA and a histone octamer connected by a linker histone H1. H1 variants are expressed in different organisms. For centromeric regions and

Various histone modifications are located at histone –NH2 or –COOH example, in humans, the histone H1 family includes the sex body tails and some histone variants form the complex histone codes. 11 different members with 7 somatic subtypes, Ubiquitination H2Aub Transcriptional silencing Mouse/spermatocyte/oocytes Baarends et al. (2005), An et al. (2010), Hasegawa et al. (2015), Luo et al. (2015) H2BK123ub Meiosis initiation and DSB Yeast Robzyk et al. (2000), Yamashita et al. (2004) formation H2BK120ub Chromatin relaxation and Mouse/spermatocyte Xu et al. (2016) homologous recombination Phosphorylation H2AT119ph Disassembly of the Drosophila/oocyte Ivanovska et al. (2005) synaptonemal complex H2AXS139ph (γH2AX) Marker of programmed Mouse/spermatocyte/oocyte Turner et al. (2005), Blanco-Rodriguez DSB and promote DSB (2012) repair in meiosis H2AS121 ph Shugoshin localization and Yeast Watanabe et al. (2012) centromeric cohesion protection in meiosis I H3S10ph Chromosome condensation Worm/tetrahymena/yeast/mammals Wei et al. (1998, 1999), Song et al. (2011) and cell division Variants H1T, TH2B, H2AX, H2AZ, Meiotic divisions and Mouse/spermatocyte Govin and Khochbin (2013), H3.3 global histone removal Montellier et al. (2013) Figure 2 Various histone modifications H3T Spermatogonial differentia- Mouse/spermatocyte Ueda et al. (2017) involved in meiosis. The major histone tion and meiosis modifications include acetylation (Ac), initiation methylation (Me), ubiquitination (Ub) and phosphorylation (P), which play important roles in meiosis. The histone sequences are derived from mammals.

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Table 1 Histone modifications and variants in the meiosis.

Modifications/variants Function Species/cells types Reference Acetylation H3K9ac, H3K18ac, H3K23ac Meiotic cell division Mouse/primary spermatocytes Song et al. (2011) H3K9ac Gene transcription Primary spermatocytes Li et al. (2017) H3K9ac Meiotic recombination Yeast Yamada et al. (2013) hotspots H3K9ac, H3K14ac, H4K5ac, Open chromatin for the Mouse/oocytes Akiyama et al. (2004), Sarmento et al. H4K8ac, H4K12ac, gene expression in GV (2004), Kageyama et al. (2007), H4K16ac oocytes Nagashima et al. (2007), Gu et al. (2010) H4K5ac, H4K8ac, H4K12ac Transcription in leptotene Mouse/spermatocytes Shirakata et al. (2014) and zygotene H4K8ac Chromatin remodeling in Mouse/oocytes Kim et al. (2003) meiosis of oocytes H4K16ac Meiotic recombination Yeast Cavero et al. (2016) checkpoint H4K44ac Facilitates homologous Yeast Hu et al. (2015) recombination Methylation H3K4me1/me2/me3 Chromatin reorganization Mouse/spermatocytes Godmann et al. (2007) H3K4me3 Programmed DSB hotspots Yeast/mouse spermatocyte/oocytes Borde et al. (2009), Buard et al. (2009), and meiotic Brick et al. (2012), Acquaviva et al. recombination initiation (2013), Sommermeyer et al. (2013) H3K9me1/me2 Synapsis and genes Mouse/spermatocyte/oocytes Tachibana et al. (2007) transcription H3K9me3 Synapsis and pericentric Mouse/spermatocyte Peters et al. (2001), Kato et al. (2015) heterochromatin modification H3K27me3 Transcriptional silencing Mouse/spermatocyte Song et al. (2011) H3K27me3 Transcription activation Mouse/oocytes Xu et al. (2016) H3K36me3 Meiotic recombination Mouse/spermatocytes Powers et al. (2016) H3K79me2 Transcriptional reactivation Mouse/spermatocytes Ontoso et al. (2014) H3K79me3 Transcription repression on Mouse/spermatocytes Ontoso et al. (2014) centromeric regions and the sex body Ubiquitination H2Aub Transcriptional silencing Mouse/spermatocyte/oocytes Baarends et al. (2005), An et al. (2010), Hasegawa et al. (2015), Luo et al. (2015) H2BK123ub Meiosis initiation and DSB Yeast Robzyk et al. (2000), Yamashita et al. (2004) formation H2BK120ub Chromatin relaxation and Mouse/spermatocyte Xu et al. (2016) homologous recombination Phosphorylation H2AT119ph Disassembly of the Drosophila/oocyte Ivanovska et al. (2005) synaptonemal complex H2AXS139ph (γH2AX) Marker of programmed Mouse/spermatocyte/oocyte Turner et al. (2005), Blanco-Rodriguez DSB and promote DSB (2012) repair in meiosis H2AS121 ph Shugoshin localization and Yeast Watanabe et al. (2012) centromeric cohesion protection in meiosis I H3S10ph Chromosome condensation Worm/tetrahymena/yeast/mammals Wei et al. (1998, 1999), Song et al. (2011) and cell division Variants H1T, TH2B, H2AX, H2AZ, Meiotic divisions and Mouse/spermatocyte Govin and Khochbin (2013), H3.3 global histone removal Montellier et al. (2013) H3T Spermatogonial differentia- Mouse/spermatocyte Ueda et al. (2017) tion and meiosis initiation

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Box 1: Acetylation Box 3: Methylation Histone acetylation is the first identified histone modification, Histone methylation is the most well-studied histone and it modulates gene transcription by fine-tuning chromatin modification, and it usually occurs on the lysine and arginine accessibility (Lee et al. 1993, Grunstein 1997, Kuo & Allis 1998, residues of histones H3 and H4 (Zhang & Reinberg 2001, Kurdistani et al. 2004). Histone acetyltransferases (HATs) and Kouzarides 2002, Bedford & Clarke 2009, Lan & Shi 2009). histone deacetylases (HDACs) are the main enzymes responsible Certain residues on histone H3 and H4 can be mono-, di- or for lysine acetylation and de-acetylation on histone N terminals tri-methylated; these modifications are catalyzed by histone respectively (Legube & Trouche 2003). It has been reported that methyltransferases (HMTs) (Santos-Rosa et al. 2002, Wang et al. the status of histone acetylation is very important to the meiotic 2003). HMTs utilize S-adenosylmethionine as their methyl group process during both spermatogenesis and oogenesis (Figs 3 and donor to modify arginine or lysine residues, thus regulating gene 4) (Hu et al. 2015, Getun et al. 2017). transcription, genome integrity and epigenetic inheritance (Bannister et al. 2002, Klose & Yi 2007). In mammals, arginine methylations of histones (H3R2, H3R8, H3R17, H3R26 and 3 testis-specific subtypes and 1 oocyte-specific H4R3) are catalyzed by protein arginine methyltransferases subtype (Izzo & Schneider 2016). Recently, a large (PRMTs). Methylations of lysine residues are catalyzed by other number of histone H1 subtype-specific modifications HMTs, including the SET-domain-containing protein family and the non-SET-domain proteins DOT1/DOT1L. These modifications have been identified by advanced mass spectrometric are considered markers for either activation or repression of the analysis, including phosphorylation, acetylation, related genes (Martin & Zhang 2005), among which, methylation, ubiquitination and ADP ribosylation methylations of H3K4, H3K36 and H3K79 are associated with (Wisniewski et al. 2007). These modifications of gene activation, whereas methylations of H3K9, H3K27 and H1 are involved in the regulation of all aspects H4K20 are responsible for gene repression (Martin & Zhang of linker histone functions. The functions of H1 2005, Klose & Yi 2007). In fact, histone methylation plays a vital phosphorylation have been extensively studied, and role in meiosis by modulating meiotic-related genes expression (Figs 3 and 4, see below). they include transcription, chromatin compaction, DNA damage and apoptosis, cell differentiation, aging and cancer (Wisniewski et al. 2007). H1 Although diverse H1 variants and modifications ubiquitination has also been reported to be essential have been investigated, their functional roles during for the initiation and amplification of ubiquitin meiosis have seldom been studied. In yeast, histone signaling after DNA damage. In this process, RNF8 is H1 is dispensable for proper meiotic recombination first recruited to DNA damage sites, and it assembles (Brush 2015), whereas in mice, H1t (Fig. 2), which a K63-linked ubiquitin chain on H1; then, RNF168 is specifically expressed in testis, is not essential for can recognize ubiquitinated H1 and catalyze the spermatogenesis because H1t knockout has no effect ubiquitination of H2A to recruit related DNA repair on the development and maturation of sperm. This proteins (Thorslund et al. 2015). phenomenon might be due to the redundancy of H1 variants, because they found that once H1t was knocked out, the mRNA levels of the other H1 variants were all Box 2: Ubiquitination increased (Drabent et al. 2000). The H1 ubiquitination Ubiquitination is a ubiquitous PTM that participates in many E3 ligase RNF8 is also not essential for meiosis, since biological events (Hershko & Ciechanover 1998, Beck-Sickinger Rnf8-deficient male mice showed no significant & Mörl 2006). Ubiquitination is achieved by a cascade of abnormalities during spermatocytes meiosis (Lu et al. enzymatic reactions that are sequentially catalyzed by ubiquitin- 2010). These findings indicate that the physiological activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and function of this H1 PTM and H1 variants during meiosis ubiquitin ligase (E3) (Callis 2014). Conversely, deubiquitinating still need further investigation. enzymes (DUBs) can remove the ubiquitin molecules (or chains) from the modified substrates Komander ( et al. 2009, Isono & Nagel 2014). Targets or substrates can be modified by one Box 4: Phosphorylation ubiquitin molecule (mono-ubiquitination) or by an ubiquitin chain (poly-ubiquitination). Different linkages inside the Phosphorylation is one of the most significant post- ubiquitin chain define its topology, which determines the final transcriptional modifications, and it plays inimitable roles in destination of the modified proteins (substrates) Hershko( & various cellular processes. The functional roles of Ciechanover 1998). For example, K48-linked ubiquitin chains phosphorylation are mainly achieved by activating or usually guide modified proteins to proteasome for degradation. inactivating its downstream factors or by recruiting related K63-linked ubiquitin chains are thought to be involved in proteins. Particularly, histone phosphorylation has diverse protein–protein interactions in a number of important signaling functions in DNA damage repair, gene transcription and pathways (Komander 2009). The major form of histone chromatin condensation (Wei et al. 1999, Ivanovska et al. 2005, ubiquitination during meiosis is mono-ubiquitination, which Bell et al. 2011, Lange et al. 2011). During meiosis, histone functions to regulate gene transcription and change or to phosphorylation can facilitate DSB formation and repair during reshape the chromatin structures to facilitate meiotic progression homologous chromosome synapsis and recombination (Lan et al. 2016, Li et al. 2017). (Perez-Cadahia et al. 2010, Bell et al. 2011).

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Figure 3 Patterns of histone modifications involved in meiosis during spermatogenesis. Spermatogenesis is a well-regulated process that starts from the self-renewal of type A spermatogonia and then differentiates into type B spermatogonia. Type B spermatogonia generate preleptotene spermatocytes, and then enter meiosis. Programmed DSB formation and homologous recombination takes place in the zygotene and pachytene stages, and their repairment is finished in the diplotene/ diakinesis stage. The secondary spermatocytes that originate from the segregation of the homologous chromosomes generate the haploid round spermatids after meiosis II. Afterward, round spermatids enter the spermiogenic phase and finally transform into spermatozoon. The sketch represents the patterns of histone modifications, which are involved in meiosis and spermatogenesis.

The histone codes of H2A in meiosis are arrested at the pachytene stage, the arrest is mainly caused by defected sex chromosome segregation and Among the four core histones, H2A contains the largest impaired MLH1 foci formation (Celeste et al. 2002). number of variants, including H2A.X, H2A.Z, MacroH2A, Phosphorylation of histone H2AX on S139 ( H2AX) H2A.Lap1, TH2A and H2A-Bbd (Monteiro et al. 2014, γ is a crucial histone code for programmed DSB repair. Shinagawa et al. 2015). During meiosis, H2A.X mainly Once the programmed DSB is formed, H2A.X is rapidly participates in homologous recombination in the early phosphorylated ( H2AX) by protein kinases ATM and stage of prophase I. Further investigation found that γ ATR (Rogakou et al. 1998, Stiff et al. 2004, Lee et al. H2ax-knockout female mice are fertile, albeit litter size 2014, DeLoughery et al. 2015). H2AX signal is very was smaller than the control group, while the H2ax- γ important for the rapid activation and recruitment of knockout male mice are infertile, and the spermatocytes

Figure 4 Patterns of histone modifications involved in meiosis of oogenesis. Oogenesis is a special gametogenesis process that is characterized by the presence of two growth arrests and two asymmetric divisions. The first arrest is at GV phase, which will be resumed again after birth. Some histone modifications are involved in the meiotic resumption process. After the GVBD stage, there are two successive asymmetric nuclear divisions to generate matured oocyte. The mature oocytes then arrested at metaphase II. That is the second arrest, and will be reactivated by the sperm after fertilization. www.reproduction-online.org Reproduction (2017) 154 R65–R79

Downloaded from Bioscientifica.com at 10/03/2021 12:59:21AM via free access R70 L Wang, Z Xu and others programmed DSB repair proteins, including MDC1, proteins to the damage site, such as proteins 53BP1 and BRCA1, 53BP1 and RAD51, to the damage sites; these BRCA1 in somatic cells (Ma et al. 2011, Mallette et al. proteins further relax the chromatin around the damage 2012). The absence of RNF168 impairs long-term sites to promote effective DSB repair (Paull et al. 2000, spermatogenesis in 12-month-old male mice, but it has Stucki et al. 2005, Botuyan et al. 2006). Although no influence on 8-week-old male mice (Bohgaki et al. phosphorylation of H2AX is highly conserved from 2011), suggesting that the first wave of spermatogenesis yeast to mammals, the specific amino acid residue that is not affected, and the H2A ubiquitination might receives this modification differs between organisms indirectly affect meiotic recombination in an age- (Harvey et al. 2005, Moore et al. 2007). dependent manner (Nakada 2016). Polycomb repressive H2A.Z has important functions in transcriptional complex 1 (PRC1) is one of the polycomb group (PcG) regulation and is enriched on transcription start sites complexes in mammals, and it can catalyze mono- (TSS). During meiosis, the expression of H2A.Z is ubiquitination of H2A at lysine 119 (H2AK119ub) to increased in the pachytene stage, when meiotic sex suppress the expression of large numbers of genes during chromosome inactivation (MSCI) occurs, peaking development (Bohgaki et al. 2011). Sex comb on midleg- at the round spermatid stage, indicating that H2A.Z like 2 (SCML2) is a germline-specific subunit of PRC1, participates in the process of silencing sex chromosomes and it can promote RNF2-dependent ubiquitination of (Greaves et al. 2006, Guillemette & Gaudreau 2006). In H2A to mark somatic/progenitor genes on autosomes Arabidopsis thaliana, H2A.Z is associated with meiotic for repression. SCML2 can also recruit USP7, a recombination hot spots, and the mutation of ARP6, deubiquitinase, to the XY body in spermatocytes, thereby which is required for H2A.Z deposition, reduces the preventing RNF2-dependent ubiquitination of H2A on number of crossover, DMC1 or RAD51 foci, suggesting sex chromosomes during meiosis and enabling unique that H2A.Z promotes the formation or processing of epigenetic programming of sex chromosomes for male meiotic DNA DSBs (Choi et al. 2013). H2A.Z is also reproduction (Nakagawa et al. 2008, Hasegawa et al. essential for pericentric heterochromatin integrity and 2015, Luo et al. 2015). UBR2, an N-end rule proteolytic sister chromatid cohesion formation, and the deletion pathway ubiquitin ligase, can also catalyze H2A of H2A.Z results in defective chromosomal segregation ubiquitination by promoting the HR6B (E2)–H2A (Rangasamy et al. 2004). In female mice, H2A.Z is interaction and the HR6B-to-H2A transfer of ubiquitin. highly expressed during GV, GVBD, MII oocytes and UBR2-deficient spermatocytes are profoundly impaired the blastula stage. However, the precise roles of H2A.Z in chromosome-wide transcriptional silencing of genes in oocyte maturation and differentiation are largely linked to unsynapsed axes of the X and Y chromosomes unknown (Wu et al. 2014). (An et al. 2010). Some other H2A variants have also been identified In addition, the phosphorylation of H2A Thr119 has in meiosis. MacroH2A, is enriched on inactive X been reported to be required for proper chromosomal chromosomes and is capable of mediating X chromosome architecture establishment in Drosophila oocytes, which inactivation in both males and females by setting up a is mediated by nucleosomal histone kinase-1 (NHK-1), repressive chromatin environment (Angelov et al. 2003, and H2AT119 phosphorylation is also essential for Mietton et al. 2009). A novel H2A histone variant, H2A. synaptonemal complex disassembly and chromosome Lap1, has also been identified, and it is dynamically condensation during meiosis (Ivanovska et al. 2005). loaded onto the inactive X chromosome and directly H2AS121 can be phosphorylated in yeast during opens the chromatin structure of the TSS, enabling the meiosis, and this phosphorylation is mediated by BUB1 transcriptional activation of previously repressed genes (Kawashima et al. 2010). H2AS121 phosphorylation during spermatogenesis (Soboleva et al. 2012). TH2A might be important for shugoshin localization, and it is and TH2B are highly expressed in testis. Disruption required for centromeric cohesion protection in female of the Th2a and Th2b genes results in sterility due to meiosis I (Watanabe 2012). The Bub1-H2Aph-Sgo1 incomplete release of cohesin at interkinesis after pathway is highly conserved from yeast to mammals, meiosis I and the failure of histone replacement during albeit the phosphorylation site is T120 in humans spermiogenesis (Shinagawa et al. 2015). (Kawashima et al. 2010). As the first identified ubiquitination substrate, the physiological function of H2A ubiquitination remained unknown for a long time. In the DSB response signal The PTMs of histone H2B during meiosis pathway, H2A ubiquitination plays a key role in the transduction of the damage signals and recruitment of Both ubiquitination and phosphorylation of histone repair proteins. This H2A ubiquitination is mediated H2B have been identified to play important functional by RNF168, which can add K63-linked ubiquitin roles in meiosis (Fig. 2). Mono-ubiquitination of H2B on chains on H2A or H2AX and is assisted by UBC13 (E2) K120 has been found to peak in spermatocytes, and the (Mattiroli et al. 2012). H2A ubiquitination is crucial for RNF20/RNF40 complex is the E3 ligase responsible for recruiting downstream DNA damage response (DDR) the mono-ubiquitination of H2BK120 (Zhang & Yu 2011,

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Xu et al. 2016). Germ cell-specific knockout of Rnf20 and zygotene stages, acetylated H3 lysine 9(K9) and results in the complete blockage of spermatogenesis. lysine 18(K18) are abundant in chromatin. In fission Therefore, RNF20-mediated H2BK120 mono- yeast, H3K9ac is enriched at meiotic recombination ubiquitination is indispensable for spermatogenesis. hotspots, and the absence of H3K9ac reduces the Further investigations reveal that this modification levels of the DSB-inducing protein Rec12 and DSB at mainly participates in meiotic recombination by hotspots, indicating that H3K9ac may be involved in promoting chromatin relaxation in the pachytene stage, DSB formation by enhancing the interaction between and a similar regulation mechanism is highly conserved Rec12 and hotspots (Hansen et al. 2011, Yamada et al. in yeast. Furthermore, H2B ubiquitination has been 2013). When spermatocytes enter the pachytene stage, reported to be involved in the initiation of programmed the meiotic genes are inactivated by a decreased DSBs during meiosis in yeast (Fig. 3) (Yamashita et al. bonding of H3K9ac and H3K18ac, suggesting that these 2004); while, this function may not apply to meiosis in modifications might also be involved in the meiotic genes mammals. transcription regulation (Khalil et al. 2004, Song et al. Histone H2BS10 phosphorylation in yeast occurs 2011, Shirakata et al. 2014). The level of H3K18ac in a cell cycle-dependent manner and peaks in the has been found to increase again in the diplotene and pachytene stage. This modification has been reported diakinesis stages (Khalil et al. 2004, Song et al. 2011), so to affect chromosomal condensation (Ahn et al. 2005). it is speculated that H3K18ac may also be required in However, this type of potential function in mammals the following meiotic events. still needs to be investigated. In females, in addition to the leptotene stage, there is large-scale gene transcription at the diplotene stage of oogenesis (Edwards 1965). A large amount of mRNAs The histone codes of H3 during meiosis for essential proteins in oocyte maturation and zygote The histone codes of histone H3 have been well studied, development after fertilization are synthesized during the including acetylation, methylation, phosphorylation and GV phase (De La Fuente 2006, Virant-Klun et al. 2013). some of its variants (Fig. 2), and their functional roles H3K9ac and H3K14ac exist in these active transcription will be introduced one-by-one in the following sections. regions to create a microenvironment for recruiting transcriptional factors and RNA polymerase II at the GV stage in oocytes (Kim et al. 2003, De La Fuente et al. 2004, Gu et al. 2010, Ding et al. 2012). After meiosis resumes Histone H3 acetylation in meiosis at the GVBD stage, these acetylations are removed by Many of the lysine residues presented on H3 can be histone deacetylases (HDACs) to further condense the acetylated. The acetylations of K9, K14, K18 and K56 chromatin for meiotic division (Akiyama et al. 2004, have been reported to be involved in various aspects Ma & Schultz 2016). of meiosis. Acetylated H3 lysine 56 (H3K56ac) can be detected in the premeiotic S phase and persists during Histone H3 methylation during meiosis meiotic recombination in budding yeast. A histone chaperone, ASF1, is necessary for H3K56ac, as the Histone H3 is the major target of methyltransferase. disruption of Asf1 causes the disappearance of this Lysines 4, 9, 27, 36 and 79 of H3 can be modified by modification. In C. elegans, the mutants of two C. elegans different histone methyltransferases (HMTases), and they Asf1 homologs, ASFL-1 and UNC-85, influence DNA mainly exert their functions in the pachytene stage. replication in the germline (Grigsby et al. 2009). In The methylations of H3K4, H3K9 and H3K36 have addition, the absence of ASF1B in mice delays the been detected on meiotic chromatin from leptonema meiosis initiation both in males and female, while the (Hochwagen & Marais 2010, Grey et al. 2011, subsequent gonad development is affected more severely Powers et al. 2016). Recent studies also reveal that H3K4, in Asf1b-null female mice than that in male mice, thus H3K9 and H3K36 could be methylated by PR domain- resulting in the reproductive capacity were severely containing 9 (PRDM9, also known as Meisetz) and that reduced in females (Messiaen et al. 2016). H3K56 they participate in meiotic recombination initiation in acetylation is also necessary for genome stability and spermatocytes (Powers et al. 2016). PRDM9 is a hotspot chromosome assembly in response to DNA damage in marker protein of meiotic recombination initiation yeast (Recht et al. 2006, Simoneau et al. 2015). In mice, (Berg et al. 2010, Parvanov et al. 2010, Grey et al. H3K56ac, together with H3K9ac, has been reported to 2011, Brick et al. 2012, Wu et al. 2013, Pratto et al. participate in DSB repair possibly by relaxing chromatin 2014, Sun et al. 2015, Patel et al. 2016). Direct binding structures on the damage sites (Masumoto et al. 2005, of PRDM9 to the 13-mer hotspot DNA motif mainly Tjeertes et al. 2009, Battu et al. 2011, Guo et al. 2011, depends on its C2H2 Zinc finger domain (Hayashi et al. Gong & Miller 2013, Zhong et al. 2016), suggesting a 2005, Myers et al. 2008), while the PR/SET domain is similar mechanism might exist during programmed DSB responsible for methylating many histone lysine residues. initiation and meiotic recombination. At the preleptotene H3K9 can also be methylated by G9a and Suv39h. www.reproduction-online.org Reproduction (2017) 154 R65–R79

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G9a is a major mammalian H3K9 methyltransferase, Histone H3 phosphorylation during meiosis G9a depletion impairs H3K9 (me1/3) methylation and During oocyte maturation, HASPIN-mediated H3T3 results in abnormal meiotic homologous recombination, phosphorylation is required for meiotic resumption and which leads to the failure of spermatogenesis anaphase onset (Nguyen et al. 2014, Wang et al. 2016). (Tachibana et al. 2001, 2007, Takada et al. 2011). In addition, phosphorylation of histone H3 at S10 is Suv39h has 2 isoforms, and Suv39h2 is highly expressed another important modification for oocyte maturation in adult testis (O’Carroll et al. 2000). Suv39h catalyzes that ensures proper chromosomal condensation the methylation of H3K9 at a specific stage in which and subsequent segregation. The absence of H3S10 the spermatogonia transform into spermatocytes, and phosphorylation inhibits meiosis and causes defects in Suv39h is mainly responsible for pericentric H3K9 meiotic chromosome condensation and segregation in methylation. Loss of Suv39h results in nonhomologous both Tetrahymena and worms (Wei et al. 1998, 1999, interactions and impaired synapsis, particularly for Hsu et al. 2000). Furthermore, H3S10 phosphorylation the sex chromosomes. The depletion of Suv39h also was detected in yeast and mammals during meiosis impedes chromosome segregation and specialized (Song et al. 2011), so we speculate that H3S10 chromatin structure formation (Peters et al. 2001). In phosphorylation might be essential for meiotic division addition, the cooperation of H3K4 methyltransferase during meiosis in an evolutionary conserved manner. Set1C/COMPASS and the Mer2/Mei4/Rec114 complex have been found to promote meiotic homologous recombination (Nottke et al. 2011, Sommermeyer et al. Histone H3 variants in meiosis 2013). In yeast, histone methyltransferase Dot1 works together with H3K79me to participate in a meiotic The variants of histone H3 play essential roles in every recombination checkpoint. If meiotic DSBs were stage of spermatogenesis. H3.3 is an evolutionarily unrepaired and/or interhomolog interactions are faulty, conserved variant involved in transcriptional regulation Dot1-dependent H3K79me can exclude Pch2 from the (Sakai et al. 2009). Histone variant H3.3 is encoded by chromosomes and promote Mek1 autophosphorylation, two genes in the mouse, H3f3a and H3f3b, but they have thereby driving Hop1 localization along chromosome different functions during gametogenesis, as knockouts axes and activating the pachytene checkpoint to trigger of either of these genes cause different phenotypes. Adult downstream responses (Ontoso et al. 2013). Dot1L- and female H3f3a mutants are fertile, while male H3f3a Dot1L-mediated H3K79methylation are essential for mutants are subfertile with abnormal sperm, which is oogenesis, as any impairment of them results in oocyte mainly caused by impaired transformation from round to arrest at metaphase of meiosis I (Wang et al. 2014). elongated spermatids. Loss of H3f3b is lethal (Tang et al. The ESET/SETDB1 complex is a methyltransferase for 2015). A decreased level of H3.3b results in remarkable H3K9me2 in oocytes, and it has irreplaceable functions enrichment of H3K9me3 in spermatogonia and in pre- in oocyte maturation. Deficiency ofSetdb1 greatly leptotene, leptotene, zygotene and early (stage I–V) impairs oocyte maturation, meiosis resumption, spindle pachytene spermatocytes during spermatogenesis, and formation and distribution, and also chromosome it not only disrupts the transcription of related genes but dynamics (Eymery et al. 2016, Kim et al. 2016). also changes chromosome structures, thereby inhibiting Many histone H3 methylation have been found to be histone replacement (Yuen et al. 2014). In addition, the involved in MSCI. For instance, H3K4me3 disappears functional roles of H3.3 in nucleosome replacement from the XY body, while H3K9me3, H3K27me3 after MSCI or meiotic silencing of unsynapsed chromatin and H3K36me3 are accumulated on it, and all of might be evolutionary conserved from fly to mammals them can indicate the transcriptional silencing state (van der Heijden et al. 2007, Sakai et al. 2009). H3.3 of spermatocytes (Berletch et al. 2010, Boggs et al. is also essential for oogenesis. Conditional ablation of 2002). H3 lysine79 methylation (H3K79me1, me2 and H3f3b at the beginning of the folliculogenesis stage me3) may also be involved in MSCI maintenance. The results in zygote cleavage failure, while simultaneous distribution of all three types of H3K79me is diverse ablation of H3f3a and H3f3b in the folliculogenesis during spermatogenesis. Lower levels of H3K79me1 are stage leads to primary oocyte death (Tang et al. 2015). found in the prophase spermatocytes, while H3K79me2 Recently, a new H3 variant, H3t, was found in mice. and H3K79me3 levels start to increase at the pachytene H3t has a counterpart H3.4 (H3T) in humans, and both stage. H3K79me3 is enriched on the heterochromatic of them are specifically expressed in testis, especially centromeric regions and XY body, while H3K79me2 in B-type spermatogonia and early-stage spermatocytes. is detected on all chromatins except the XY body. During spermatogonia differentiation, H3t replaces Therefore, H3K79me3 and H3K79me2 may have canonical H3 proteins, thus forming a more open antagonistic functions, H3K79me3 may be involved in chromatin structure. H3t (H3T) containing nucleosomes MSCI and centromeric region repression and H3K79me2 are required for spermatogonial differentiation, and is related to transcriptional reactivation on autosomes ensure entry into meiosis, as H3t gene deficiency (Ontoso et al. 2014). leads to male infertility due to the failure of germ cell

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Downloaded from Bioscientifica.com at 10/03/2021 12:59:21AM via free access The histone codes for meiosis R73 differentiation from spermatogonia to spermatocytes in the diplotene and diakinesis stages (Khalil et al. 2004, (Ueda et al. 2017). Song et al. 2011), indicating that H4K16ac may also be CENPA is another histone H3 variant that is involved in the following events during meiosis. specifically localized at the centromeres and modulates In females, high levels of H4K5ac, H4K8ac, their behavior (Niikura et al. 2015). Recently, CENPA has H4K12ac and H4K16ac can be detected on meiotic been reported to participate in meiotic recombination chromosomes (Kim et al. 2003, De La Fuente et al. by recruiting RAD51 to the nuclear periphery in a 2004, Kageyama et al. 2007, Gu et al. 2010, Ding et al. SAC- and a DDR-dependent manner in C. elegans germ 2012). They are necessary for the resumption of meiosis cells (Lawrence et al. 2015). In humans, a novel H3 at the GVBD stage. In addition, H4 deacetylation, variant, H3.5, has been found to accumulate around including H4K8, H4K12, H4K14 and H4K16, is then the TSS region in human testis, forming an unstable accompanied by two asymmetric meiotic divisions, and nucleosome. This variant might be involved in regulating inadequate meiotic histone deacetylation may result in chromatin dynamics during human spermatogenesis aneuploidy and embryo abnormality (Akiyama et al. (Urahama et al. 2016). 2006, Ma & Schultz 2013). In Hdac2-knockout mouse oocytes, the hyperacetylation of H4K16 impairs kinetochore function, with unstable microtubule The PTMs of histone H4 during meiosis attachments and less CENPA located at the centromeres, The PTMs of histone H4 play important roles in almost thereby causing defective chromosome condensation all stages of meiosis (Fig. 2). During the proleptotene and segregation (Ma & Schultz 2013). During human and the zygotene stages, H4 lysine 5, 8, 12 and 16 are oocyte maturation, abundant H4K12ac is closely linked acetylated and are concentrated on chromatin. They to chromosome misalignment (van den Berg et al. were reported to participate in gene transcription during 2011), further indicating that normal deacetylation is many cellular processes. For example, H4K5ac has been important for normal oocyte development. H4K20me3 reported to promote the expression of cognitive-related is also required for proper chromosome alignment genes (Park et al. 2013). Therefore, we speculate that they and polar body extrusion during meiosis I, because might be involved in male meiotic gene transcription knockdown of Suv4-20h, an H4K20 methyltransferase, (Khalil et al. 2004, Song et al. 2011, Shirakata et al. remarkably decreases H4K20me3, resulting in a high 2014). In yeast, H4K44ac is predominantly enriched proportion of abnormal meiotic metaphase I oocytes at meiotic recombination hotspots during meiosis. The (Xiong et al. 2013). absence of H4K44ac results in increased nucleosomal occupancy around DSB hotspots, indicating that H4K44ac is essential for normal DSB formation and Cross-talk among the histone codes meiotic recombination by facilitating chromatin Phosphorylation, acetylation, methylation and accessibility (Hu et al. 2015). Recently, it was revealed ubiquitination are the most important PTMs of histones that several histone H3 and H4 acetylations harbored during meiosis, many modifications often occur on open and active chromatin regions promote the simultaneously in the same events, or even at the same recruitment of PRDM9 and Spo11, thereby facilitating sites of histones, and they interact and influence each programmed DSBs formation at the leptotene stage and other to ultimately determine the meiotic process. crossover resolution at the pachytene stage (Getun et al. The PRC1 and PRC2 complexes can regulate gene 2016) (Fig. 3). transcription during meiosis, and their functions are During the zygotene stage, H4K5ac, H4K12ac and mainly modulated by cross-talk between H2AK119 H4K16ac maintain relatively higher levels. H4K16ac has ubiquitination and H3K27me3. First, the PRC2 been reported to participate in DSB repair by relaxing complex is loaded onto the chromatin that catalyzes chromatin around the DNA damage sites (Tjeertes et al. H3K27 trimethylation, which, in turn, recruits PRC1 to 2009, Battu et al. 2011, Guo et al. 2011, Gong & Miller ubiquitinate H2AK119; this ubiquitination is important for 2013, Zhong et al. 2016). polycomb group (PcG)-mediated silencing (Margueron & During the pachytene stage, transcriptional Reinberg 2011, Cooper et al. 2016). Furthermore, NHK- repression first initiates on the XY body. The methylation 1-mediated H2AT119 phosphorylation is a prerequisite and acetylation of H4 might be involved in MSCI. for H3K14 and H4K5 acetylation, and the disruption H4K20me3, H4K12ac and H4K16ac are excluded of NHK-1 results in the loss of H3K14ac and H4K5ac from the X and Y chromosomes, while H4K5ac and (Ivanovska et al. 2005). Recently, we also found that H4K8ac persist on them, suggesting that H4K5ac and H2BK120 ubiquitination affects H3K14ac (marker H4K8ac might be involved in MSCI formation during of loosened chromatin) and H3K4me2 (marker of meiosis; however, their real functions still need further condensed chromatin) on autosomes (Xu et al. 2016), investigation (Vaskova et al. 2010, Lawrence et al. indicating an interplay of these modifications during 2015). It is noteworthy that H4K16ac is increased again meiosis. As increased studies focus on this aspect, more www.reproduction-online.org Reproduction (2017) 154 R65–R79

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(6) With the development of chromosome conformation capture techniques (3C) to 4C, 5C and Hi-C, can these regulations be investigated in a three- dimensional manner in the near future? The abovementioned questions definitely need further investigation, and the answers to these questions will help us to understand their relationships and the exact regulating mechanisms of meiosis. Histone codes are used to write an elegant program to direct complex meiotic process, and the dissection of these codes will shed light on various aspects of meiosis.

Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding This work was supported by the National Natural Science Foundation of China (grants 91519317, 91649202 and 31471277) and National Key R&D Program of China (grant 2016YFA0500901).

Acknowledgement The authors apologize to the colleagues whose work could not be cited due to space limitation.

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