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(The FASEB Journal. 1999;13:89-93.)
© 1999 FASEB

Research Communications

Reduced levels of poly(ADP-ribosyl)ation result in chromatin compaction and hypermethylation as shown by cell-by-cell computer-assisted quantitative analysis

Adriana De Capoaa, Francesca Romana Febboa, Federica Giovannellia, Alain Niveleauc, Giuseppe Zardob, Stefania Marenzib and Paola Caiafad,1

a Department of Genetics and Molecular Biology, University of Rome La Sapienza Rome, Italy
b Department of Biochemical Sciences `A. Rossi Fanelli', University of Rome La Sapienza Rome, Italy
c CNRS UPRES-A 5082, Department Virologie, Facultè de Medicine, Université Joseph Fourier, Grenoble, France
d Department of Biomedical Sciences and Technologies, University of L'Aquila, I-67100 L'Aquila, Italy


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The unmethylated status of the CpG islands is important for gene expression of correlated housekeeping genes since it is well known that their methylation inhibits transcription process. An interesting question that has been discussed but not solved is how the CpG islands maintain their characteristic unmethylated status even though they are rich in CpG dinucleotides. Our previous in vitro and in vivo research has shown that poly(ADP-ribosyl)ation is involved in protecting CpG dinucleotides from full methylation in genomic DNA and that a block of poly(ADP-ribosyl)ation is also involved in modifying the methylation pattern in the promoter region of Htf9 housekeeping gene. In this study we locked for cytological evidence that in the absence of an active poly(ADP-ribosyl)ation the DNA methylation pattern in L929 and NIH/3T3 mouse fibroblast cell lines is altered. For this purpose, differences in the methylation levels of interphase nuclei from control and treated cultures of two murine cell lines preincubated with 2 mM 3-aminobenzamide, an inhibitor of poly(ADP-ribosyl)ation, were measured in individual cells after indirect immunolabeling with anti-5MeC antibodies. The quantitative analysis allowed us to demonstrate that blocking of the poly(ADP-ribosyl)ation results in a higher number, size, and density of antibody binding regions in treated cells when compared to the controls. Analogously, sequential Giemsa staining and indirect immunolabeling of the same slides showed the heterochromatic regions colocalized with the extended methyl-rich domains.—de Capoa, A., Febbo, F. R., Giovannelli, F., Niveleau, A., Zardo, G., Marenzi, S., Caiafa, P. Reduced levels of poly(ADP-ribosyl)ation result in chromatin compaction and hypermethylation as shown by cell-by-cell computer-assisted quantitative analysis. FASEB J. 13, 89–93 (1999)


Key Words: 3-ABA • 5-methylcytosine • poly(ADP-ribose)poly-merase


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
POLY(ADP-RIBOSYL)ATION IS ONE of the postsynthetic modifications that has been identified as being greatly involved in some important biological processes (1–15) and that recent research has shown to be an enzymatic mechanism that plays a controlling role in maintaining the methylation pattern in eukaryotic DNA (16, 17). This DNA methylation pattern, which is defined during embryonic development (18), is very important since a characteristic of this pattern is that some DNA regions located in the 5' promoter region of housekeeping genes, and termed CpG islands (19, 20), are present in their unmethylated status, this condition being essential for the expression of correlate genes (21–23). How these regions manage to preserve this unmethylated status, notwithstanding being rich in CpG dinucleotides and being located in a decondensed chromatin structure where the DNA methyltransferase has easy access, has yet to be explained. Regarding the CpG islands, recent research (16, 17) has shown that the inhibition of poly(ADP-ribosyl)ation allows the new methyl groups to position themselves in DNA.

The purpose of the present work is to provide cytological evidence that the DNA methylation pattern of L929 and NIH/3T3 mouse fibroblast cell lines is altered by inhibition of poly(ADP-ribosyl)ation. Through the use of anti-5-methylcytosine (5MeC)2 monoclonal antibodies and peroxidase-tagged second antibodies on cells previously preincubated with 3-aminobenzamide (3-ABA), a well-known inhibitor of poly(ADP-ribose) polymerase (24), we illustrate the relationship between these two important nuclear processes. In this experimental approach, the antibodies also become a probe to investigate another important biological question: whether increased levels of DNA methylation are directly related to an increase in chromatin condensation in interphase nuclei.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Two fibroblastoid cell lines, L929 and NIH/3T3, were grown in a BHK21 medium with the addition of 10% newborn calf serum and 2 mM glutamine in a humidified 5% CO2 atmosphere at 37°C (16). Exponentially growing cells were preincubated with 3-ABA for 24 h to the final concentration of 2 mM. Cytological preparations were obtained from cell suspensions by pelleting and suspension steps in isotonic solution, then fixed in a 1:3 acetic acid/methanol mixture. No hypotonic solution was used. Cells were spread on glass slides by a standard air-drying technique. The slides were kept at room temperature for 2 wk, then aged for 48 h in an oven at 50°C before immunolabeling.

Specimens were exposed to UV under a germicidal lamp in order to denature DNA, according to the standard procedure originally developed by Schreck et al. (25) for metaphase chromosomes. The cells were then incubated with monoclonal anti-5MeC antibodies as previously described (26). Binding of anti-5MeC antibodies was detected with peroxidase-tagged goat anti-mouse second antibodies (Bio-Rad, Milano, Italy). Alpha-chloronaphtol (4ClN) was used as the substrate. No counterstain was used. Slides from control and treated cultures were simultaneously processed throughout the entire procedure in order to minimize technical bias. Nuclei were observed with an Orthomat Leica microscope (obj.40.x) and images were registered by a b/w CCD camera (VC-44, Kelheim, Germany).

The global methylation status of individual nuclei in treated and control cultures was assessed on CCD camera images by dedicated software (Image Pro Plus 3.1, Media Cybernetics, Silver Spring, Md.). All slides were analyzed for the following parameters: average number, area, and optical density (OD) of the ab-positive heterochromatic regions, according to a previously published protocol (27).

Colocalization of heterochromatic and anti-5MeC-positive regions was evaluated on cytological preparations from NIH/3T3 cells. For this purpose, cytological preparations were stained with Giemsa (Merck) and a first set of digitized images was registered. Each slide was then destained in 70% ethanol for 10 min before labeling cells with anti-5MeC antibodies. The fields selected in the previous step were relocated under the objective lens, and new images were acquired and registered with the CCD camera. This approach allowed us to analyze the nuclear localizations of both the heavily blue-stained heterochromatic regions and the binding sites of anti-5MeC antibodies.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Experimental conditions performed to induce the blockage of poly(ADP-ribosyl)ation were the same as those in which the absence of an active poly(ADP-ribose) polymerase allowed the introduction of new methyl groups into both genomic (16) and CpG islands DNA (17). Since by treating the cells with 8 mM 3-ABA an effect of the mono(ADP-ribosyl)ation process on DNA methylation cannot be excluded (28) in these experiments, unlike those previously reported (16, 17), we used a lower 2 mM 3-ABA concentration to specifically inhibit the poly(ADP-ribose) polymerase.

Results obtained with nuclei from L929 cells show significant differences between controls and treated samples with regard to the average values of number, area, and OD of ab-positive heterochromatic regions, as shown in Table 1. The same effect was observed in NIH/3T3 cells ( Table 2). Therefore, we can conclude that the treatment with 3-ABA is positively correlated with a significant increase in the amount of bound anti-5 MeC monoclonal antibodies. This result is illustrated in Fig. 1, which shows that nuclei from controls ( Fig. 1a, b) clearly contain less condensed immunolabeled `spots' that nuclei from treated cultures ( Fig. 1c, d). Furthermore, the OD of these condensed regions is higher than that of their untreated counterparts.


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  		Table 1. L929 cell line1tfa


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  		Table 2. NIH/3T3 cell line2tfa



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  		Figure 1. CCD camera images showing the binding sites of anti-5MeC antibodies to the heterochromatic regions of control (a) and 3-ABA-treated (c) cells from L929 and NIH/3T3 control (b) and treated (d) cultures.

Giemsa-stained heterochromatic areas and ab-positive regions are colocalized, as illustrated by Fig. 2, where images of the same field observed after each staining protocol are displayed side by side for control ( Fig. 2a, b) and treated NIH/3T3 cells ( Fig. 2c, d). These results also show that anti-5MeC antibodies can reach their target within heterochromatic regions, in agreement with previously published data on intense heterochromatin labeling by anti-5MeC antibodies (26, 27).



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  		Figure 2. CCD camera images of sequentially Giemsa-stained and immunolabeled NIH/3T3 nuclei. Giemsa staining of control (a) and treated (c) nuclei and immunolabeling of the same control (b) and treated (d) cells.

When treated cells are compared with controls, one can see that the area covered by condensed chromatin is enlarged by a factor between 3 and 4, whereas the number of dense `spots' is increased by only 59% and 88% for L929 cells and NIH/3T3cells, respectively. Therefore, one can reasonably assume that inhibition of poly(ADP-ribosyl)ation results in an extension of preexisting condensed chromatin domains and that this extension is accompanied by increased 5MeC immunolabeling.

No gross morphological alterations were observed in treated cells. A similar size distribution was observed in control and treated cells for both cultures. Treating the cells with a higher 3-ABA concentration (8 mM) yielded results similar to those described above. One can conclude, therefore, that the effects observed here are not due to an increase in the size of nuclei induced by the treatment.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The use of monoclonal antibody anti-5-methylcytosine allowed us to obtain information about both the hypermethylation present on DNA after treatment of cells with 3-ABA and how an increased level of methylation can be related to chromatin condensation in interphase nuclei.

Results obtained from colocalization analysis in the NIH/3T3 cell line show that, on cytological grounds, the compacted heterochromatin domains have the same geographic distribution within each nucleus as the methyl-rich regions. These results suggest a strict correlation between the two phenomena.

Treated nuclei consistently show larger areas and often higher numbers of deeply Giemsa-stained heterochromatic regions. This indicates that, after the inhibition of poly (ADP-ribosyl)ation, nuclear chromatin is induced to aggregate in a highly condensed structure. This suggests that heterochromatinization spreads out preferentially from a preexisting condensed center and that methylation takes part in this process. These results indicate that DNA hypermethylation of cells treated with 3-ABA is established during 3-ABA treatment. This effect represents a preexistent condition with respect to that reported in our endogenous methyl-accepting ability experiments (16), in which the incorporation of labeled methyl groups (60% higher in the DNA from 3-ABA treated cells than in DNA from controls) is indicative of further DNA capability to be methylated.

The whole of our results based on different experimental strategies (16, 17), including the use as a probe of anti-5MeC antibodies, leads us to the conclusion that the poly(ADP-ribosyl)ation reaction is definitely involved in protecting the DNA methylation pattern.

Since control of the DNA methylation pattern occurs somewhere along a chain of events, it is extremely difficult to identify in which step of the chain the modification intervenes with its regulatory role.

Two hypotheses can be considered: there is a direct interaction between DNA and some proteic factor in its poly(ADP-ribosyl)ated isoform; and the interaction is indirect since the poly(ADP-ribose) polymerase is involved in modifying proteins that are only indirectly involved in the DNA methylation process. An example of the first hypothesis is H1e in its poly(ADP-ribosyl)ated isoform (16), which may inhibit the methyltransferase activity on DNA (29, 30) In this case, it is impossible to exclude the involvement of other proteins able to bind methylated DNA sequences (31–43). An example of the second hypothesis is that poly(ADP-ribosyl)ation may modulate the binding of proliferating cell nuclear antigen with DNA methyltransferase or in facilitating the competitive binding of p21 for the same site (44, 45).

As for chromatin condensation, it is important to remember that, in our experimental model, DNA hypermethylation was induced by a block of poly(ADP-ribosyl)ation and that this postsynthetic modification is also involved in modulating chromatin structure (46). In fact, poly(ADP-ribosyl)ation of H1 histone (1–3, 5), and particularly of the H1e variant (46), has been reported to induce chromatin decondensation. One possibility is that the modification plays this role by preventing those H1-H1- interactions that are very important for attaining a higher order of chromatin structure (47–50).

Previous in vitro experiments indicated that the H1e variant was the only genic variant of the H1 histone family capable of inducing formation of H1-H1 polymers and that the same variant, enriched in its poly(ADP-ribosyl)ated isoform, loses this ability (46). We can hypothesize that (in our experiments) after the inhibition of poly(ADP-ribose) polymerase, the physiological amount of H1e in its poly(ADP-ribosyl)ated isoform is substituted by histone H1e ADP-ribose free isoform so that the condensing effect of this protein is able on its own to enhance chromatin condensation.

The results reported here not only provide evidence for increased DNA methylation after exposure to 3-ABA, as shown by Zardo et al. (16), but demonstrate that variations in 5MeC detection and in chromatin compaction can be observed and quantified at a cytological level on a cell-by-cell basis. Together, these new results open the field to a method to achieve discrimination, within a single sample, between various subpopulations of nuclei displaying different methylation levels.


   ACKNOWLEDGMENTS
 
This work was supported by the Italian Ministry of University and Scientific and Technological Research (40% Progetti di Interesse Nazionale, 60% Ricerca Scientifica dell'Università dell'Aquila e dell'Università La Sapienza Roma) and by the Galileo Italian-French Exchange Program. We thank Rosa Clara Traversi and Alessandra Spanò for skilled technical assistance in the preparation step.


   FOOTNOTES
 
1 Correspondence: Dipartimento di Scienze e Tecnologie Biomediche, Università dell'Aquila; Via Vetoio, Loc. Coppito, I-67100 L'Aquila, Italy. E-mail: caiafa{at}axscaq.aquila.infn.it

2 Abbreviations: 3-ABA, 3-aminobenzamide; 5MeC, anti-5-methylcytosine; OD, optical density.

Received for publication July 20, 1998. Revision received September 12, 1998.
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 ABSTRACT
 INTRODUCTION
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 DISCUSSION
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C. J. Piyathilake and G. L. Johanning
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M. A. KARYMOV, M. TOMSCHIK, S. H. LEUBA, P. CAIAFA, and J. ZLATANOVA
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C. Nguyen, G. Liang, T. T. Nguyen, D. Tsao-Wei, S. Groshen, M. Lubbert, J.-H. Zhou, W. F. Benedict, and P. A. Jones
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Evaluation of global DNA hypomethylation in human colon cancer tissues by immunohistochemistry and image analysis
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J. ZLATANOVA, P. CAIAFA, and K. VAN HOLDE
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G. ZARDO, S. MARENZI, M. PERILLI, and P. CAIAFA
Inhibition of poly(ADP-ribosyl)ation introduces an anomalous methylation pattern in transfected foreign DNA
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