Molecular Human Reproduction, Vol. 9, No. 12, pp. 757-763, 2003
© European Society of Human Reproduction and Embryology 2003; all rights reserved
Misregulation of histone acetylation in Sertoli cell-only syndrome and testicular cancer
1Unité INSERM U309, Université Joseph Fourier, Institut Albert Bonniot, Faculté de Médecine de Grenoble, Domaine de la Merci, 38706 La Tronche Cedex, 2Laboratoire de Biologie de la Reproduction, Centre Hospitalier Universitaire de Grenoble, BP 217, 38 043 Grenoble Cedex 09, 3Laboratoire de Biologie de la Reproduction, INSERM GDPM, Université Paris V, CHU Cochin, 24 rue du Faubourg Saint-Jacques, 75014 Paris and 4Service d’Anatomie Pathologique, Centre Hospitalier Universitaire de Grenoble, BP 217 38043 Grenoble Cedex 09, France 5Current address: Département de Biologie, Université Libanaise, Faculté des Sciences II-Fanar, Lebanon
6 To whom correspondence should be addressed. e-mail: sophie.rousseaux{at}ujf-grenoble.fr
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Abstract |
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In many species, including humans, chromatin remodelling during spermiogenesis is initiated with a marked increase in histone acetylation in elongating spermatids. We have investigated whether this process is disturbed when spermatogenesis is defective or in human testicular tumours. For this purpose, the presence of highly acetylated histone H4 was detected on testicular sections from men with a severe impairment of spermatogenesis of several origins, as well as in different types of testicular tumours. In most tubules devoid of germinal cells (including SCO, Sertoli cell only syndromes) or lacking spermatocytes and spermatids, the Sertoli cells’ nuclei showed a global increase in histone H4 acetylation. A similar observation was made in the peritumoral seminiferous tubules of testicular tumour tissues, whenever they were lacking germinal cells, with carcinoma in situ (CIS) cells being hypoacetylated. The global hyperacetylation of elongating spermatids during spermatogenesis could be part of an intercellular signalling pathway involving Sertoli cells and germinal cells, which could be disturbed in cases of severe spermatogenesis impairment, as well as in tubes surrounding germ cells in testicular tumours.
Key words: chromatin remodelling/human/Sertoli cells/spermatogenesis/testicular cancer
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Introduction |
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Evidence exists to support the concept that undescended testis, poor semen quality and testicular cancer are symptoms of an underlying ‘testicular dysgenesis syndrome’. This syndrome is becoming increasingly common due to adverse environmental effects, and could result from disruption of gonadal development during fetal life (reviewed by Skakkebaek et al., 2001). Nothing is known yet about the biological mechanisms underlying this syndrome, which are likely to involve disruptions of both processes of testis differentiation and spermatogenesis (Skakkebaek, 2002). Since changes in chromatin structure have been demonstrated in many cellular differentiation processes, as well as in the generation of certain cancers, we decided to explore some aspects of chromatin remodelling during normal and pathological spermatogenesis.
Acetylation of the N-terminal tail of the core histones, the main protein component of chromatin in somatic cells, is involved in epigenetic signalling pathways, regulating various cellular physiological processes, including gene expression, chromatin assembly and cell proliferation, as well as some pathological processes such as tumorigenesis (Kuo and Allis, 1998; Archer and Hodin, 1999; Strahl and Allis, 2000; Turner, 2000). In mammalian spermatogenesis, hyperacetylation of the core histones occurs during spermiogenesis. At this stage, the nucleus is subject to many changes in its structure, the most spectacular being its remodelling during the post-meiotic maturation of spermatids into sperm. During this process, the nucleosomal organization of chromatin is first erased and histones are removed, while transition proteins and then protamines appear and finally the spermatid genome is packed into the highly condensed sperm nucleus (Kierszenbaum, 2001; Boissonneault, 2002; Meistrich et al., 2003). This results in a specific packaging of the DNA and a highly condensed chromatin in the mature sperm head (Balhorn, 1982). Immediately before their displacement, the core histones have been shown to be highly acetylated in several species including rooster, trout, rat and mouse (Christensen et al., 1984; Grimes and Henderson, 1984; Oliva and Mezquita, 1982; Meistrich et al., 1992; Hazzouri et al., 2000) suggesting an involvement of histone acetylation in the series of events initiating the post-meiotic remodelling of the spermatid nucleus.
In order to gain an understanding of the role of histone acetylation during human spermatogenesis in normal and pathological testes, we have detected in situ by immunohistochemistry the pattern of histone acetylation during human normal spermatogenesis. We then investigated whether the physiological variations in core histone acetylation during normal spermatogenesis could be disturbed in different testicular pathological processes, including impaired spermatogenesis and testicular cancers. For this purpose, the pattern of histone H4 acetylation was studied in testicular biopsies of infertile patients with altered spermatogenesis of different causes, as well as in several types of testicular tumours.
We initially confirmed that in humans, as in many other species, the core histones are hyperacetylated in late round and early elongating spermatids, just before their replacement. Unexpectedly, the nuclei of Sertoli cells were shown to be hyperacetylated in response to an absence of germinal cells in the seminiferous tubules, supporting evidence that an intercellular signalling pathway, through global core histone acetylation, is involved in normal and pathological spermatogenesis. Moreover, in peritumoral carcinoma in situ (CIS)-containing tubules, Sertoli cell nuclei were also hyperacetylated, suggesting that this abnormal pattern of histone acetylation in Sertoli cells could participate in the genesis of testicular cancers.
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Materials and methods |
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Patients
Testicular biopsies of 36 patients, aged between 30 and 58 years, were studied. These patients underwent testicular biopsies in the context of either a severe impairment of spermatogenesis (27/36) or a testicular tumour (6/36). The testicular biopsies were provided by the Urology Department.
Four testis sections with normal or subnormal spermatogenesis were used as controls.
Twenty-seven testicular tissues originated from infertile patients, who were affected by a defective spermatogenesis and were either azoospermic or severely oligozoospermic (Table I). The infertility was idiopathic in two cases and a related clinical condition was identified in 25 cases: cryptorchidism (n = 18), ectopic testis (n = 1), hormonal abnormality (n = 2), genetic disorder (n = 3), varicocele (n = 1). Thirteen biopsies showed a complete absence of germinal cells (or SCO: Sertoli cell-only syndrome), and 14 a severe hypospermatogenesis with an arrest at a specific stage (five arrests after the spermatogonial stage, two arrests after the spermatocyte stage, and seven arrests after the spermatid stage).
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Six testicular tissues originated from patients with testicular tumours: choriocarcinoma (testis A), embryonal carcinoma (testis B), immature teratoma (testis C), diffuse large B cell lymphoma (testis D), and two seminomas (testes E and F) (Table II).
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Immunohistochemistry
The highly acetylated form of the core histone H4 (acH4) was detected by immunohistochemistry on human paraffin-embedded testis sections (fixed in Bouin or MFA: 80% methanol, 15% formol and 5% acetic acid), using a polyclonal rabbit immunoglobulin G raised against acH4 (Upstate Biotechnology, USA) as a primary antibody, according to a protocol described previously (Hazzouri et al., 2000).
Slides analysis
A cytological analysis of the slides was systematically achieved by two different operators, and confirmed by a pathologist. The somatic and germinal cells were identified by their position in seminiferous tubules and by their morphology in haematoxylin–eosin staining. A brown nuclear staining identified the positive cells. The proportion of labelled cells, as well as the intensity of the labelling, were evaluated on each slide.
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Results |
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Acetylation of histone H4 during normal spermatogenesis
Histone H4 acetylation during normal spermatogenesis was analysed in seminiferous tubules from testis from three control subjects (patients 28, 29 and 30) as well as in the subnormal peritumoral region of testis C containing the immature teratoma (see below). A specific pattern was observed in all four testes (Table III: testicular histology ‘normal’).
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A global acetylation was observed in the nuclei of most of the spermatogonia (affecting 80, 50, 100 and 80% of the spermatogonia of testis sections of patients 28, 29, 30 and C respectively). It was then followed by a deacetylation during meiosis in all the spermatocytes of the seminiferous tubules. The chromatin was found again globally highly acetylated in all elongating spermatids, whereas no signal was observed in condensing spermatids. These patterns are shown in Figure 1a and b.
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The pattern of histone H4 acetylation in Sertoli cells was also assessed as shown in Figure 1a and b. All the nuclei of the Sertoli cells were negative on the testis tissues from patient 28, whereas 10, 20 and 30% of the Sertoli cell nuclei of the testis sections from patients 29, 30 and testis C respectively were weakly positive for the staining.
Acetylation of histone H4 in testicular tissues from patients with altered spermatogenesis
In order to investigate whether an impairment of spermatogenesis could disturb the chronology of acetylation throughout spermatogenesis, we studied testicular tissues from 27 oligozoospermic or azoospermic patients with an arrest of spermatogenesis at different stages and in different clinical contexts. The results of these experiments are described in Table III.
In tubes with residual spermatogenesis showing a meiotic or post-meiotic arrest (an arrest at the spermatocyte ‘Spc arrest’ or spermatid ‘Tid arrest’ stages)
In nine testicular tissues, the seminiferous tubules contained spermatocytes and/or spermatids (these include two testis biopsies with an arrest after the spermatocyte stage and seven with an arrest after the spermatid stage).
In these tissues, the pattern of acetylation observed in the nuclei of the germinal cells was similar to that obtained during normal spermatogenesis (Figure 1c and d). Indeed, the spermatogonia were positive in the testicular tissues of five patients among the nine, whereas most of the spermatocytes remained negative. In three testis biopsies, 10–30% of the spermatocytes presented a positive signal. Histone H4 was again acetylated in the nuclei of elongating spermatids in six biopsies among the seven presenting an arrest after the spermatid stage, with an intense labelling similar to that observed during normal spermatogenesis. The testicular section in which elongating spermatids were negative (patient 16), showed labelling neither in germinal cells nor in the tissue surrounding the seminiferous tubules (this biopsy was the only one showing no labelling at all, and a non-accessibility of the antibody to its antigen could not be ruled out).
In the two tissue samples originating from the patients with an arrest at the spermatocyte stage (patients 9 and 22), most of the Sertoli cell nuclei were negative (only 10% of the cells were weakly labelled with the antibody in testis section from patient 9). Among the seven testis sections with a spermatid arrest, all Sertoli cells from three biopsies were negative (patients 15, 16 and 27), one biopsy contained a few weakly positive Sertoli nuclei (patient 24), and in three biopsies, most of the Sertoli nuclei were weakly positive (patients 10, 12 and 17). Altogether, the nuclei of the Sertoli cells were negative or weakly positive in seminiferous tubules containing spermatocytes and/or spermatids (Figure 1c and d).
In tubes devoid of spermatogenic cells (‘SCO’ tubes), or containing no spermatogenic cells beyond the spermatogonial stage (‘Spg arrest’)
Eighteen testicular biopsies contained some tubes with very few germinal cells (arrest after the spermatogonial stage, n = 5) or presented a complete absence of germinal cells in all the seminiferous tubule sections (SCO syndrome, n = 13). These tubes contained an increased number of Sertoli cells, compared with that of tubes with normal or residual spermatogenesis.
In four testis tissues with an arrest after the spermatogonial stage, most of the spermatogonia were positive with the antibody, while in testicular sections from patient 20, only 20% of the nuclei of spermatogonia were labelled (Figure 1e).
The pattern of histone H4 acetylation of the Sertoli cell nuclei was intriguing in these tissues (Figure 1e, g and h). In the five testicular biopsies presenting an arrest after the spermatogonial stage, most Sertoli cells were strongly positive, showing a massive increase in acetylation of their chromatin. In 12 SCO syndrome testes, most of the nuclei of the Sertoli cells again showed an intense labelling with the antibody. In one testicular tissue sample (patient 7), only 10% of the nuclei of the Sertoli cells were positive, but the signal was again strong.
Testes from patients 12 and 15 showed on the same slides tubes containing hypospermatogenesis (with an arrest after the spermatid stage) and tubes devoid of germinal cells (SCO tubes). In tubes with spermatid arrest, 60% of the Sertoli cells of testis tissue of patient 12 were labelled, but the signal was weak, and Sertoli cells of patient 15 were all negative. In contrast, in the SCO tubes from both patients, 90% of the Sertoli nuclei were strongly positive.
Acetylation of histone H4 in testicular tumours and in peritumoral tissues
In order to investigate the role of histone acetylation in testicular carcinogenesis, six types of testicular cancers were studied.
In testicular tumours cells
Among the six testicular tumours studied here, four had tumour cells, which did not show any hyperacetylation of H4 (Table III: ‘cancer cells’ column, see patients C, B, E, F, A and D). Indeed, all tumour cells from the immature teratoma (testis C), the embryonal carcinoma (testis B), one of the two seminomas (testis E) and the diffuse large B-cell lymphoma (testis D) were negative (Figure 2). In the choriocarcinoma (testis A), the nuclei of tumour cells were strongly labelled with the acH4 antibody (Figure 2a). In one of the two seminomas (testis F), a few tumour cells (20%) were positive but the signal was weak (Figure 2f).
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In peritumoral seminiferous tubules
In some of these testes (testes C, B, E and F), some remnant seminiferous tubules were present on the testis sections around the tumoral tissues. The peritumoral tubules from three testes (B, E and F) contained CIS cells, which are pre-tumoral cells lining the basement membrane of the tubes, and showed severely impaired spermatogenesis (SCO tubes). In testes B, E and F, all CIS cells were negative, suggesting that their chromatin was not globally acetylated but 70% of the nuclei of the Sertoli cells clearly showed intensely positive nuclei (Figures 1f and 2g, h). This hyperacetylation of Sertoli cells was similar to that observed in patients with SCO syndrome and no tumour (Figure 1g, h).
The peritumoral seminiferous tubes on the immature teratoma (testis C) presented subnormal spermatogenesis and were devoid of CIS cells. The pattern of histone acetylation was similar in these tubes to that observed in tube sections from patients with normal spermatogenesis and no testicular tumours (control patients, see above).
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Specificity of the acetylated H4 labelling
The antibody labelled nuclei at specific stages of spermatogenesis, giving a specific staining pattern. This pattern could be explained by differences of specificity or accessibility of the antibody. However, several observations argue against this hypothesis. First, the control tissue sections treated with the preimmune serum were negative. Second, the staining pattern was restricted to some cell nuclei and did not stain other cells and the labelling was homogeneous between the different tubes on the same testis section. Hence in each testis section, the presence of both positive and negative cells could be considered as positive and negative internal controls respectively. Finally, using the same antibody, along with other specific antibodies, in immunohistochemistry, as well as in immunofluorescence and Western blot analysis experiments, a similar chronology of H4 acetylation had been observed during mouse spermatogenesis (Hazzouri et al., 2000) as here during normal spermatogenesis. Moreover, using a different antibody, Sonnack et al. (2002) have observed a similar pattern during normal human spermatogenesis.
Acetylation of core histones during normal human spermatogenesis
During mammalian spermatogenesis, most attention has been given to histone acetylation as a primary mechanism for nucleosome destabilization. Indeed immediately before their displacement, the core histones were shown to be highly acetylated in several species including rooster (Oliva and Mezquita, 1982), trout (Christensen et al., 1984), rat (Grimes and Henderson, 1984; Meistrich et al., 1992) and mouse (Hazzouri et al., 2000). Here, we confirm that this feature, which seems to be conserved through evolution, is also present during human spermatogenesis (Figure 1a and b; Table III: normal testicular histology). Moreover, our results corroborate those recently obtained by Sonnack et al. (2002), who used an antibody different from ours.
Immunohistochemistry on testicular sections or Western blot analysis of fractions of cells enriched at successive stages of spermatogenesis (as used for the detection of acetylated histone forms during mouse spermatogenesis; see Hazzouri et al., 2000), allows the detection of variations of histone acetylation which are ‘global’, involving the whole nucleus, as opposed to variations of histone acetylation observed at specific chromatin regions (i.e. euchromatic regions in somatic cells) using other molecular approaches. This phenomenon of a global increase of histone acetylation has been observed in two different situations so far: in highly replicating cells (which is probably the case for spermatogonia labelled with anti-acetylated histones here) and in elongating spermatids. In replicating cells, this observation is probably due to the fact that histones are assembled in their acetylated forms during DNA replication (Loidl and Grobner, 1987; Adams and Kamakaka, 1999). The global deacetylation observed during meiosis in spermatocytes and in round spermatids reflects a general phenomenon, which does not concern specific chromatin regions. Indeed, it is known that gene expression is active in spermatocytes as well as in round spermatids. Therefore, histone acetylation could be localized in chromatin regions rich in actively transcribing genes, which could not be detected by immunohistochemistry or on Western blots. For this reason, the hyperacetylation of histones detectable by immunohistochemistry was termed ‘global’ histone hyperacetylation.
The significance of a global and intense acetylation in the nucleus of elongating spermatids is not yet clear. Because of the fundamental role of chromatin structure during gametogenesis and on further development, we asked whether the acetylation pattern of histone H4 could be disturbed in pathological situations such as spermatogenesis deficiencies and/or testicular cancers.
Acetylation of histone H4 in testicular tissues from patients with altered spermatogenesis
Our results indicate that, in all cases of spermatogenesis impairment where spermatocytes and post-meiotic cells are absent, irrespective of the origin of the pathology, the nuclei of all or most Sertoli cells show an intense acetylation of histone H4 (Figure 1e, g and h; and Table III: ‘SCO’ and ‘Spg arrest’). By contrast, the chromatin of most Sertoli cells remains globally hypoacetylated in seminiferous tubules showing normal spermatogenesis (Figure 1a and b; and Table III: ‘normal testicular histology’) or presenting a post-meiotic arrest (Figure 1c and d; and Table III: ‘Tid arrest’ and ‘Spc arrest’). Accordingly, Sonnack et al. (2002), analysing patients with a spermatogenesis arrest during meiosis or at the spermatid stage, did not mention any change in the acetylation patterns of the Sertoli cells.
Since it is directly related to the absence of meiotic and post-meiotic cells, the increase in the global level of histone acetylation in Sertoli cells could be the result of a disturbed communication between Sertoli and germinal cells. Hence the level of acetylation of the whole nucleus could be dependent on signalling pathways involving intercellular communications. In testicular sections showing mixed atrophy (where tubules lacking germinal cells co-existed with tubules showing some spermatogenesis including spermatocytes and spermatids: testis sections from patients 12 and 15), a hyperacetylation of H4 was only observed in Sertoli cells from tubule sections with a complete lack of spermatogenesis. This suggests that a disruption of the local intercellular communication could affect the global level of histone acetylation in Sertoli cells within this particular tubule portion.
It is tempting to think that the global hyperacetylation of histones observed in elongating spermatids during normal spermatogenesis and that seen in Sertoli nuclei when spermatogenic cells are absent, are consequences of the same signalling pathway, which is normal in the former case and disturbed in the latter. For instance, the major increase in histone acetylation seen in elongating spermatids during their normal maturation could be a response to a cross-talk between Sertoli cells and spermatogenic cells.
A severe alteration of spermatogenesis is often associated with an increased risk of testicular tumours, especially in the context of a cryptorchid or ectopic testis, suggesting a link between these pathological situations. However, not much is known about the origin of testicular cancer, and the molecular reasons for this frequent association between altered spermatogenesis and testicular cancer are totally unknown (Skakkebaek, 2002; Skakkebaek et al., 2001). Variations in histone acetylation are known to be involved in the regulation of gene expression and cell proliferation, as well as in some carcinogenesis processes. This is what prompted us to investigate the pattern of H4 acetylation in testicular sections from six patients with different types of testicular tumours.
Acetylation of histone H4 in testicular tumours
Testicular tumours are the most frequent cancers in young males aged between 20 and 35 years, among which the germ cell tumours are the most common. The mechanisms involved in their pathogenesis are not yet fully understood. However, CIS cells, which consist of atypical precancer germ cells located at the basement membrane of the peritumoral seminiferous tubules, are now accepted as the unique precursor of adult testicular germ cell tumours (Jacobsen et al., 1981; Skakkebaek et al., 1987; Dieckmann and Skakkebaek, 1999). CIS cells are suggested to pre-exist in gonads deriving from fetal germ cells rather than arising later in life (Skakkebaek et al., 1987). Since normal development of spermatogenesis partly depends on intact Sertoli cell–germ cell interaction, an impairment of this interaction could trigger and/or help the development of germ cell tumours. Indeed, of the peritumoral seminiferous tubules from the several testicular tumour types analysed here, those devoid of germinal cells and containing CIS cells showed an intense staining of Sertoli cell nuclei similar to that observed in SCO testicular sections (Figures 1f and 2g, h; Table III: SCO patients B, E and F). Therefore, it is possible that a major chromatin acetylation of Sertoli cells could in turn induce a response in the few remaining germinal cells and/or existing CIS cells, and finally result in their transformation into CIS and cancer cells. Indeed, histone post-translational modifications, and particularly acetylation, are now believed to be crucial events in signalling pathways involved in the regulation of expression of many genes, including those involved in the control of cell proliferation and the cells’ fate (Kuo and Allis, 1998; Archer and Hodin, 1999; Strahl and Allis, 2000; Turner, 2000). It is therefore conceivable that a major disturbance of the histone acetylation pattern, as observed here in tubules devoid of meiotic and post-meiotic cells, would alter one or several regulation pathways, leading to an abnormal proliferation of neighbouring and/or interacting cells.
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Acknowledgements |
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We are grateful to A.Paldi (Institut Jacques Monod, Paris) for helpful discussions and to Nathalie Bertacchi for technical assistance. This work was supported by the INSERM ‘Assistance Médicale à la Procréation’ program, by the ‘Fondation pour la Recherche Médicale’ and by the Région Rhône-Alpes ‘Emergence’ program. A.K.F. is recipient of a grant from INSERM (‘Poste d’Accueil’ programs), and M.H. was supported by the Libanese CNRS (bourse RAMMAL and programme Cèdre).
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Submitted on July 4, 2003; resubmitted on August 11, 2003. accepted on August 14, 2003
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