Histone H4



Histone H4 methyltransferase activity is cell cycle-regulated, consistent with increased H4 Lys 20 methylation at mitosis. This increase closely follows the cell cycle-regulated expression of the H4 Lys 20 methyltransferase, PR-Set7. Localization of PR-Set7 to mitotic chromosomes and subsequent increase in H4 Lys 20 methylation were inversely correlated to transient H4 Lys 16 acetylation in early S-phase. To expand the observation made in mammalian cells that H4 Lys 20 methylation decreases in S-phase and peaks at mitosis, immunofluorescence studies were performed in Drosophila embryos. A recent report shows that the H4 Lys 20-methyl modification is present in Drosophila and is essential for Drosophila development and viability (Nishioka, 2002). In addition, the embryos provide an excellent model to study H4 Lys 20 methylation during the cell cycle since they rapidly and repeatedly shift from S-phase to mitosis -- this can be easily determined by DAPI staining. Consistent with the above findings, H4 Lys 20 methylation is clearly detected on chromosomes during both metaphase and anaphase, whereas staining during S-phase results in a faint signal even upon overexposure. It is hypothesized that the faint signal during S-phase most likely reflects a combination of dilution of the modification by histone deposition as well as the decrease in chromatin condensation, which could contribute to a dispersion of the signal resulting in a decreased ability to detect the modification. Regardless, these data confirm that H4 Lys 20 methylation is decreased during S-phase and increased specifically during mitosis (Rice, 2002).


Using indirect immunofluorescence with site-specific antisera, histone H4 isoforms acetylated at lysines 5, 8, 12, or 16 have been shown to have distinct patterns of distribution in interphase, polytene chromosomes from Drosophila larvae. H4 molecules acetylated at lysines 5 or 8 are distributed in overlapping, but nonidentical, islands throughout the euchromatic chromosome arms. beta-Heterochromatin in the chromocenter is depleted in these isoforms, but relatively enriched in H4 acetylated at lysine 12. H4 acetylated at lysine 16 is found at numerous sites along the transcriptionally hyperactive X chromosome in male larvae, but not in male autosomes or any chromosome in female cells. These findings support the hypothesis that H4 molecules acetylated at particular sites mediate unique and specific effects on chromatin function (Turner, 1992).

Dosage compensation in Drosophila occurs by an increase in transcription of genes on the X chromosome in males. This elevated expression requires the function of at least four loci, known collectively as the male-specific lethal (msl) genes. The proteins encoded by two of these genes, maleless (mle) and male-specific lethal-1 (msl-1), (see Sex lethal and MSL-2) are found associated with the X chromosome in males, suggesting that they act as positive regulators of dosage compensation. A specific acetylated isoform of histone H4, H4Ac16, is also detected predominantly on the male X chromosome. MLE and MSL-1 bind to the X chromosome in an identical pattern; the pattern of H4Ac16 on the X is largely coincident with that of MLE/MSL-1. No H4Ac16 is found on the X chromosome in homozygous msl mutant males, correlating with the lack of dosage compensation in these mutants. Conversely, in Sex lethal mutants, H4Ac16 is detected on the female X chromosomes, coincident with an inappropriate increase in X chromosome transcription. These data suggest that synthesis or localization of H4Ac16 is controlled by the dosage compensation regulatory hierarchy. Dosage compensation may involve H4Ac16 function, potentially through interaction with the product of the msl genes (Bone, 1994).

MLE, MSL-1 and histone H4 acetylated at lysine 16 (H4Ac16) are located almost exclusively on the male X chromosome in interphase (polytene) cells. In neuroblasts from third instar Drosophila larva antisera to H4Ac16, MLE and MSL-1 uniquely label the distal, euchromatic region of the male X chromosome through mitosis. The centromere-proximal, heterochromatic region of the male X is not labelled with these antisera, nor are male autosomes or any chromosomes in female cells. That the association of H4Ac16 with the male X chromosomepersists, even when the chromosome is maximally compacted and transcriptionally quiescent, argues that this modified histone is an integral component of the dosage compensation pathway. In the nuclei of interphase neuroblasts from male (but never female) larva, antibodies to H4Ac16 reveal a small, brightly labelled patch against a background of generally weak nuclear staining. In double-labelling experiments, this patch was also labelled, albeit comparatively weakly, with antibodies to MSL-1. These results strongly suggest that the distal, euchromatic region of the X chromosome in male cells occupies a limited and relatively compact nuclear domain (Lavender, 1994).

To gain insights into the function of H4-K20 methylation, the highly specific methyl H4-K20-specific antibodies were used to analyze the distribution of methylated H4-K20 on Drosophila polytene chromosomes and mouse embryonic fibroblasts (MEFs). Methylation of histone H4-K20 on polytene chromosomes coincides with condensed chromosomal regions, including chromocentric heterochromatin and numerous bands on the euchromatic arms. Competition experiments were performed to verify that the observed staining pattern was specific for methyl H4-K20. In these experiments, the staining was completely removed with peptides that contained the H4 tail methylated at lysine 20, but not with unmodified peptides or by peptides that contained the H3 tail methylated at lysine 4 or lysine 9. Moreover, costaining of polytene chromosomes with antibodies raised in different organisms, a rabbit polyclonal and a mouse monoclonal antibody to methyl H4-K20, shows complete overlap (Nishioka, 2002).

Having a monoclonal antibody allowed for a direct comparison of the distribution of methylated H4-K20 with that of other modifications that occur on the H3 and H4 tails, using existing rabbit polyclonal antibodies. Comparison of the distribution of methyl H4-K20 and methyl H3-K9 on polytene chromosomes established that the H4-K20 methylation pattern is distinct from the predominantly chromocentric pattern of methylated H3-K9, a modification that has been associated with constitutive heterochromatin in various species (Nishioka, 2002).

The distribution of the methyl H4-K20 was analyzed with respect to transcriptionally active or competent genes. To accomplish this, the staining pattern on Drosophila polytene chromosomes obtained with the polyclonal antibody to methyl H4-K20 was compared to that observed with monoclonal antibody to the transcription-engaged form of RNA polymerase II. This analysis demonstrated nonoverlapping patterns for each of the antibodies in the entire chromosomes, except at regions that were not fully spread; this led to the conclusion that methylated H4-K20 was very low or absent from transcriptionally competent regions. Similar results were obtained when the staining pattern of the antibody to methyl H4-K20 was compared to that of the transcriptionally active form of RNA polymerase II at heat shock loci under heat shock (transcriptionally permissive) conditions (Nishioka, 2002).

To further analyze the association of the methyl H4-K20 mark with transcriptionally silent chromatin, the methyl H4-K20 staining pattern was compared to that obtained with antibodies specific to methyl H3-K4, a mark that has been correlated with transcriptionally competent genes in higher eukaryotes. Consistent with the results with RNAPII staining, nonoverlapping patterns for methyl H3-K4 and methyl H4-K20 were observed in the entire polytene chromosomes, except at regions that were not fully spread. Thus, it is concluded that the methylated H4-K20 modification marks transcriptionally silent chromatin (Nishioka, 2002).

Oogenesis and Spermatogenesis

There are two distinct phases of histone gene expression during oogenesis. In the first phase, which occurs during early to middle oogenesis (stages 5-10A), there is a mosaic pattern of histone mRNA in the 15 nurse cells of the egg chamber: some cells have very high levels of mRNA, while others have little or no mRNA. This analysis suggests that there is a cyclic accumulation and subsequent degradation of histone mRNA in the egg chamber and that very little histone mRNA is transported into the growing oocyte. Moreover, since the endomitotic replication cycles of the nurse cells are asynchronous during this period, the mosaic distribution of histone message would suggest that the expression of the histone genes in each nurse cell nucleus is probably coupled to DNA replication as in most somatic cells. The second phase begins at stage 10B. During this period, histone gene expression appears to be "induced" in all 15 nurse cells of the egg chamber; instead of a mosaic pattern, high levels of histone mRNA are found in all cells. Unlike the earlier phase, this expression is apparently uncoupled from the endomitotic replication of the nurse cells (which are completed by the end of stage 10A). Moreover, much of the newly synthesized histone mRNA is transported from the nurse cells into the oocyte where it accumulates and is stored for use during early embryogenesis. Tightly clustered grains are observed within nurse cell nuclei in non-denatured tissue sections. As was the case with cytoplasmic histone mRNA, there is a mosaic distribution of nuclear grains from stages 5 to 10A, while at stage 10B, virtually all nurse cell nuclei have grain clusters. These grain clusters appear to be due to the hybridization of nurse cell histone gene DNA to the histone mRNA probe, and are localized in specific regions of the nucleus (Ambrosio, 1985).

Relatively low levels of histone mRNAs are present in egg chambers prior to stage 10, during the period of nurse and follicle cell polyploidization. Histone mRNAs accumulate rapidly and selectively after stage 10, coinciding with the onset of nurse cell degeneration and well after DNA synthesis and actin mRNA accumulation have ceased. A large proportion of the histone mRNAs is associated with polysomes at all times, indicating that expression of histone genes is not strictly coupled to DNA synthesis. Another burst of histone mRNA accumulation near the end of oogenesis may provide a store of maternal histone mRNA to support the rapid cleavages that occur during early embryogenesis (Ruddell, 1985).

A genomic fragment was cloned from a DNA library constructed from a Drosophila enhancer trap line in which reporter gene expression was observed at the anterior-most tip of the ovaries and testes. This genomic clone was identified as the L-repeat of the Drosophila melanogaster histone gene cluster. Northern blotting and in situ hybridization to RNA in tissues with individual cDNAs and PCR-generated probes for each histone confirm that gene expression is greatest at the anterior portion of each ovariole, in the germarium, and is also elevated in a few individual nurse cells and somatic follicle cells within the egg chamber during early developmental stages. Histone H1 and each of the core histones have a similar expression pattern that is correlated to cell division. Maternal stores of histone transcripts are also transported to the mature oocyte from the nurse cells at a later stage of oogenesis (stage 10), when virtually all the nurse cells contain high levels of histone transcripts. The results are consistent with expression of the somatic histone gene cluster during oogenesis as a coordinate unit. There does not seem to be a reduced level of somatic type H1 in the germ-line, as is observed in some other species. The relationship between the P[lacZ] expression pattern in the germarium and the overall expression of the histone cluster suggests there are specific regulatory elements for germ-line expression (Walker, 1998).

maleless (mle) is essential in Drosophila melanogaster males both in somatic cells and in germ cells. In somatic cells mle is necessary for X-chromosome dosage compensation. The role of mle in the germline is unknown. The expression pattern and localization of MLE, the other MSLs and acetylated isoforms of histone H4 in male germ cells have been examined to address whether dosage compensation and/or X inactivation occur in the Drosophila germline. MLE is the only MSL expressed in the male germ cells and is not localized to the X chromosome, nor with any other chromosomal cluster. Weak Mle expression is detectable in spermatogonia and early spermatocytes. Mel is very abundant in the nuclei of fully developed primary spermatocytes; it continues to be detectable in round stage spermatids and elongated spermatides. Mle protein is not detectable during later stages of spermatid development. Studies using a mle temperature sensitive allele reveal that, genetically, the amount of mle activity required for fertility is higher than that required for viability. The analysis of mle mutant gonads reveals that complete loss of mle in the germline and in the soma does not affect the development of male germ cells. Spermatogeneisis can proceed to the final stages of differentiation in the apparent absence of Mle protein. In male germ cells, loss of mle has no detectable effect on the expression or localization of Histone H4 acetylated on amino acid 16. The lack of specific X chromosome localization of H4Ac16 in the transcriptionally active stages of spermatogenesis argues against a role of H4Ac16 in dosage compensation and favors a more general role in transcriptional activation. It is concludedthat in the germline mle is not involved in chromosomal dosage compensation but, in its requirement for male fertility, may be involved inpost-transcriptional gene regulation, perhaps mediated by the Mle helicase function. The acetylation pattern of histone H4 is verydynamic during spermatogenesis. While the pattern is not compatible with dosage compensation or Xinactivation, it is consistent with all premeiotic chromosomes being in an active configuration that isreplaced in post-meiotic stages with an inactive chromatin constitution (Rastelli, 1998).

Transition from a nucleosome-based to a protamine-based chromatin configuration during spermiogenesis in Drosophila

In higher organisms, the chromatin of sperm is organised in a highly condensed protamine-based structure. In pre-meiotic stages and shortly after meiosis, histones carry multiple modifications. This study focused on post-meiotic stages and shows that also after meiosis, histone H3 shows a high overall methylation of K9 and K27; it was hypothesised that these modifications ensure maintenance of transcriptional silencing in the haploid genome. Furthermore, histones are lost during the early canoe stage, and just before this stage, hyper-acetylation of histone H4 and mono-ubiquitylation of histone H2A occurs. It is believed that these histone modifications within the histone-based chromatin architecture may lead to better access of enzymes and chromatin remodellers. This notion is supported by the presence of the architectural protein CTCF, numerous DNA breaks, SUMO, UbcD6 and high content of ubiquitin, as well as testes-specific nuclear proteasomes at this time. Moreover, the first transition protein-like chromosomal protein to be found in Drosophila, Tpl94D, is reported. It is proposed that Tpl94D (an HMG box protein) and the numerous DNA breaks facilitate chromatin unwinding as a prelude to protamine and Mst77F deposition. Finally, it is showm that histone modifications and removal are independent of protamine synthesis (Rathke, 2007).

The switch between a nucleosome-based chromatin configuration and a protamine-based structure is a specialised form of chromatin remodelling in the male germline. The mammalian zinc finger protein CTCF is involved in many epigenetic processes. Furthermore, paralogous variant of CTCF which is testis-specifically expressed, called BORIS, is exclusively expressed in the mammalian male germline. The function of BORIS in this context is still not clear. Drosophila, in contrast to mammals, contains only one CTCF gene. It was therefore asked whether Drosophila CTCF is also expressed in the testes, and immunostaining and anti-histone staining was performed on testes of transgenic flies expressing protamine-eGFP. CTCF expression was observed during pre-meiotic and meiotic stages at the chromosomes as has been shown for mitotic cell division in mammalian cell culture. Shortly after meiosis, CTCF is visible in young elongating nuclei, where it co-localises with the chromatin as indicated by the histone distribution. CTCF is also present in the early and late canoe stage spermatid heads. At the early canoe stage, CTCF is very diffusely distributed in comparison to histones. CTCF does not co-localise with the chromatin which starts to condense at one side of the nucleus. This diffuse distribution is still visible at the late canoe stage when protamine-eGFP starts to be deposited to the chromatin. CTCF is no longer detectable after the canoe stage. The earlier chromatin-associated CTCF localisation might indicate a very early role in chromatin reorganisation at the switch between the nebenkern and canoe stage. Furthermore, CTCF might be associated primarily with the chromatin, which is not yet condensing during these stages. The late canoe stage is the only post-meiotic stage where distinct regions of RNA polymerase II are found with an antibody directed against a phosphorylated subunit of active polymerase, indicative of transcription. At this precise stage, only a very small set of genes is thought to be transcribed. Also CTCF expression during chromatin reorganisation in the nucleus was detected in D. hydei (Rathke, 2007).

Sperm morphogenesis is characterised by an impressive degree of changes in cell architecture based on stored, translationally repressed mRNAs that are recruited at the appropriate time to the polysomes. Among these are mRNAs that encode Tpl94D and protamines. A dramatic switch in structure from the nucleosomal- to the protamine-based structure of chromatin takes place, and this remarkable chromatin reorganisation of the complete genome is a typical feature depending on stored mRNAs, e.g. for protamine synthesis. This process ultimately leads to an extremely condensed state of the haploid genome in the sperm, which is essential for male fertility in mammals. This study focused on the switch between a nucleosomal- and a protamine-based chromatin reorganisation. The major steps in chromatin organisation take place in the canoe stage of spermatid development. A candidate for a transition protein in Drosophila was identified. The corresponding gene tpl94D (CG31281) encodes a predicted basic high mobility group (HMG) protein of 18.8 kDa. In transgenic flies, Tpl94D-eGFP fusion proteins are expressed solely during the switch between histones and protamines, as is typical for mammalian transition proteins. Since a highly similar chain of events to those reported in mammals is observed, the Drosophila system is considered an excellent choice to study the mechanism of chromatin remodelling during male germ cell development (Rathke, 2007).

Generally, the bulk of histones, including their diverse modifications in the N-terminal tail, appear to be removed during the canoe stage. Furthermore, the nucleus accumulates ubiquitin at the early canoe stage, when mono-ubiquitylation of histone H2A is no longer detectable. Therefore, taking into account the known presence of proteasomes in the nucleus at this stage of chromatin reorganisation and the overlap of expression shown in this study, it is hypothesised that this ubiquitylation is targeting histones for degradation. This study investigated several mutants having mutations in ubiquitin-conjugating enzymes or ubiquitin ligases, exhibiting arrested spermiogenesis during spermatid development and that are male sterile. However, in all investigated mutants, histone removal is indistinguishable from that of wild-type flies (Rathke, 2007).

Many histone modifications were found after meiosis and were categorised into three classes (Rathke, 2007).

  1. Histone modifications that persist from pre-meiotic stages and keep the genome silent.

    The vast majority of the genome is transcriptionally silent in post-meiotic stages. This is accompanied by multiple histone modifications that persist from pre-meiotic stages and indicate silencing such as H3K9 and H3K27 methylation. These modifications do not change significantly during post-meiotic stages, which is in agreement with the hypothesis that these modifications predominantly play a role in maintaining transcriptional silencing. Previously, phosphorylation of histones have been analysed during spermatogenesis. Phosphorylated histone H4S1 and H3S10 are present during meiotic divisions. H3S10 phosphorylation is hardly detectable after meiosis, whereas phosphorylation of H4S1 persists until chromatin compaction starts.

  2. Histone modifications that persist from pre-meiotic stages and characterise transcriptionally active chromatin.

    The primary spermatocyte phase is characterised by a high level of transcriptional activity of housekeeping genes. In addition, genes are transcribed that are needed for the subsequent steps in spermatogenesis, as the majority of transcription ceases once meiotic division starts. H4 acetylation and H3K4 and H4R3 methylation of histones were investigated. These histone modifications, which are indicative of transcriptional activity, persist until histone degradation.

  3. Increasing or de novo appearance of histone modifications that decrease the affinity between histones and DNA as a prelude to histone removal.

    It might be that H4 hyper-acetylation, as postulated for mammals and/or other secondary modifications of histones are the first step towards histone removal. The fact that these modifications are conserved between mammals and flies adds support to this hypothesis. Indeed, histone H4 acetylation is very pronounced at the canoe stage and de novo mono-ubiquitylation of histone H2A is seen in round spermatids. Both types of histone modifications are proposed to be necessary for opening the chromatin and decreasing the contact between DNA and histones. The fact that histone H2A mono-ubiquitylation vanishes before the early canoe stage, thus before the hyper-acetylation of histone H4, leads to thinking about a stepwise remodelling of the chromatin. This study proposes that these histone modifications open the chromatin, so that enzymes and regulators have access to histone-based chromatin and can induce and prepare the reorganisation of the genome in the male germline.

It remains to be clarified whether and how these histone modifications influence the topology of the chromatin as a prelude to histone removal as well as for Tpl94D, Mst77F and protamine deposition. A functional approach based on analysis of mutants of histone-modifying enzymes is difficult, as all characterised histone-modifying enzymes are already active during Drosophila development or at least in spermatogonia and spermatocytes. Therefore a tissue-specific knock-out mutant would most probably exhibit arrest of spermatogenesis before meiosis, rendering it useless for experimental purposes (Rathke, 2007).

At the first glance, it might seem surprising that histones and all their modifications are removed. Instead of specifically reverting the differentially modified histones to their unmodified state, they are removed together with all histones. This might allow the paternal genome to form nucleosomes with unmodified histones after fertilisation and before zygote formation. Thus, the paternal genome starts embryogenesis with a nucleosomal chromatin lacking histone modifications (Rathke, 2007).

The data show that most of the histones are removed between the early and late canoe stage; such a process requires a loosening of contact between the histones and DNA, which in turn requires an unwinding of the chromatin structure. It is proposed that this unwinding process is facilitated by DNA nicks as they were widespread at this stage of chromatin reorganisation. Finally, Tpl94D, UbcD6 and SUMO were also observed to accumulate in the chromatin during this process. DNA breaks, Tpl94D, UbcD6 and SUMO were no longer detectable when protamines were fully expressed. Thus, it is proposed that all these proteins and the DNA breaks act together in an unknown manner to allow chromatin remodelling (Rathke, 2007).

The CTCF protein is present during pre-meiotic stages in the nucleus and stays associated with the chromosomes during meiosis. After meiosis, however, strong localisation to the nucleus is detected during the transition from round spermatid nuclei to the early canoe stage of spermiogenesis. It is speculated that CTCF might set borders in the chromatin for the histone modifications, which are characteristic of the canoe stage, such as acetylation and ubiquitylation. CTCF is visible for longer than histones and disappears together with active RNA polymerase II. CTCF might maintain chromatin accessibility to RNA polymerase II since a few genes are known to be transcribed at this time. In addition, transient occurrence of RNA polymerase II at the late canoe stage might require CTCF to insulate active genes from inactive ones. This idea needs to be tested in tissue-specific CTCF loss-of-function mutants; such mutants are, however, currently unavailable (Rathke, 2007).

The question of whether histone removal is dependent on a signal that monitors the start of protamine and Mst77F mRNA translation was addressed. Both histone modification and degradation are indistinguishable from the wild-type in loss-of-function mutants of Mst35Ba and Mst35Bb, the genes encoding protamine A and B, respectively. Also in nc3 mutants of Mst77F, histone removal is not disturbed. It is concluded that N-terminal tail modification of histones and histone degradation, on the one hand, and protamine deposition, on the other, are controlled by different pathways in the cell (Rathke, 2007).

In mammals, it is well known that after meiosis the nucleosomal conformation is lost. This is accompanied by the appearance of testis-specific linker histones. So far, no linker histone variants have been identified in Drosophila, but variants of H2A (H2AvD) and H3 (H3.3) are known. In mammals, histones are hyper-acetylated before being displaced from the DNA, and phosphorylation and ubiquitylation have also been proposed to occur. For Drosophila, H2A mono-ubiquitylation and a strong increase in H4 acetylation occur shortly before histone removal and degradation. In mammals, histones are replaced first by transition proteins (major types: TP1 and TP2). This study identified the high mobility group protein Tpl94D, a first probable candidate for a functional homologue of mammalian transition proteins. In mammals, transition proteins are subsequently replaced by protamines leading to chromatin with a doughnut structure. In Drosophila, it has recently been shown that the sperm nucleus also contains protamines. Protamines A and B are encoded by two closely related protamine genes, Mst35Ba and Mst35Bb. In addition, the identification of Mst77F shows that sperm nuclei contain at least one further abundant chromatin component. Moreover, in human sperm several new putative protamines have been identified by 2D gel electrophoresis and protein sequencing. In mammals, this chromatin reorganisation is essential for male fertility. Male flies carrying the deletion protDelta38.1, where both protamines as well as three additional ORFs are removed, show severely reduced fertility (Rathke, 2007).

In summary, a step-by-step scheme is proposed for chromatin reorganisation: (1) histone modifications lead to subsequent histone removal and degradation; (2) the exposed chromatin becomes nicked, resulting in DNA breaks; (3) Tpl94D deposition constitutes an intermediate stage that triggers subsequent protamine-based chromatin organisation (Rathke, 2007).

Since many features concerning spermiogenesis are conserved between Drosophila and mammals, it is proposed that Drosophila is an ideal system to gain further insight into the mechanism of chromatin reorganisation in spermatid nuclei, a process that is crucial for male fertility (Rathke, 2007).


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Histone H4: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology

date revised: 26 December 2020

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