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(The FASEB Journal. 2009;23:672-678.)
© 2009 FASEB

Epigenetics: poly(ADP-ribosyl)ation of PARP-1 regulates genomic methylation patterns

Paola Caiafa1, Tiziana Guastafierro and Michele Zampieri

Department of Cellular Biotechnology and Haematology, Second Faculty of Medicine and Surgery, University "La Sapienza," Rome, Italy; and Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy

1Correspondence: University of Rome "La Sapienza," Department of Cellular Biotechnology and Haematology, Viale Regina Elena, 324, 00161 Rome, Italy. E-mail: caiafa{at}bce.uniroma1.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PARYLATION
 DNA METHYLATION
 CROSSTALK BETWEEN PARYLATION AND...
 CTCF ACTIVATES PARP-1
 CONCLUSIONS
 REFERENCES
 
In the postgenome era, attention is being focused on those epigenetic modifications that modulate chromatin structure to guarantee that information present on DNA is read correctly and at the most appropriate time to meet cellular requirements. Data reviewed show that along the chain of events that induce DNA methylation-dependent chromatin condensation/decondensation, a postsynthetic modification other than histone acetylation, phosphorylation, and methylation—namely poly(ADP-ribosyl)ation (PARylation)—participates in the establishment and maintenance of a genome methylation pattern. We hypothesize that the right nuclear balance between unmodified and PARylated poly(ADP-ribose) polymerase 1 (PARP-1), which depends on the dynamics of PARPs/PARG activity, is key to maintaining genomic methylation pattern. According to our data, decreased or increased levels of PARylated PARP-1 are responsible for diffuse hypermethylation or hypomethylation of DNA, respectively. In our model, polymers present on PARP-1 interact noncovalently with DNA methyltransferase 1 (Dnmt1), preventing its enzymatic activity. In the absence of PARylated PARP-1, Dnmt1 is free to methylate DNA; if, in contrast, high levels of PARylated PARP-1 persist, Dnmt1 will be stably inhibited, preventing DNA methylation.—Caiafa, P., Guastafierro, T., Zampieri, M. Epigenetics: poly(ADP-ribosyl)ation of PARP-1 regulates genomic methylation patterns.


Key Words: imprinting • CTCF • Dnmt1 • CpG islands


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PARYLATION
 DNA METHYLATION
 CROSSTALK BETWEEN PARYLATION AND...
 CTCF ACTIVATES PARP-1
 CONCLUSIONS
 REFERENCES
 
THE TERM "EPIGENETICS" COVERS all those phenomena that control the functional state of DNA without changing the DNA sequence (i.e., without inducing genetic mutation). Among these, postsynthetic modifications of DNA and of histone tails are of extreme importance because by interfering with chromatin structure, they determine its remodeling, which is necessary to modulate the accessibility to information that is present on DNA. Through specific interactions with chromatin proteins, the 2 meters of human DNA, which are contained in cell nuclei of a few micrometers’ diameter, become part of an ordered structure that is more or less prone to allow gene expression as a function of its architecture. The fact that the DNA molecule is not only great in size but also in the number of functions it carries out makes it even more difficult to understand how, being in so complex a structure, it is able to satisfy all needs at any required time according to the cell’s necessity. To explain the "omnipotence" of DNA, attention is being focused on the study of those epigenetic processes which, without modifying the genetic code, allow DNA to guarantee the normal flux of events during cellular life.

These modifications, distributed on DNA and proteins in a nonrandom fashion, constitute an epigenetic code, extending the information of the genetic code (1) .

Recently, poly(ADP-ribose) polymerase (PARP) activity has been implicated in multiple pathways that regulate gene expression, including but not limited to effects on chromatin structure (2 3 4) and transcriptional activator and coactivator functions (5) . Our findings add another dimension to the regulatory functions of poly(ADP-ribosyl)ation (PARylation) through affecting DNA methylation patterns. However, it is not demonstrated that PARylation is part of the epigenetic code yet.


   PARYLATION
TOP
 ABSTRACT
 INTRODUCTION
 PARYLATION
DNA METHYLATION
 CROSSTALK BETWEEN PARYLATION AND...
 CTCF ACTIVATES PARP-1
 CONCLUSIONS
 REFERENCES
 
The reason that the possible epigenetic marks introduced by PARylation are difficult to decode lies in the complexity of this enzymatic reaction (6 7 8 9) .

PARylation carries out a plethora of cellular functions, which explains the high abundance of PARP molecules in the cells; only a small fraction of them are present in their PARylated form. The presence of numerous inactive PARP molecules guarantees an immediate response to cell signaling or DNA damage (10 11 12) . In fact, when cells are fighting for survival in adverse conditions, the level of long ADP-ribose polymers (PARs) is dramatically increased (by ~500 times); however, they are quickly degraded as their half-life goes down from 6–7 min to a few seconds. The few PARP molecules that are modified under normal conditions are those involved in housekeeping roles; the half-life of polymers on molecules involved in housekeeping functions is several hours (8) .

PARPs are enzymes that covalently build PARs on chromatin proteins, among which are the PARPs themselves. PARPs use the respiratory coenzyme NAD+ as a source of ADP-ribose moieties to synthesize protein-bound polymers of variable size (from 2 to more than 200 residues) and structural complexity (linear or branched) (7 8 9) . The intracellular level of PARs is under tight control of the poly(ADP-ribose) glycohydrolase (PARG), the enzyme that cleaves the ribose-ribose bonds of PARs both endo- and exonucleolitically (13) (Fig. 1a ). The process by which PARPs introduce covalently bound PARs onto other proteins is known as heteromodification, whereas automodification is the process by which PARPs introduce covalently bound PARs onto themselves (Fig. 1b ). PARs, both protein-free and covalently linked on proteins, are also capable of strong noncovalent binding (12 , 14) with specific proteins, whose activity is modulated by the highly negatively charged bound polymers. PARP-1, the main member of the PARP family (6) , provides several examples of biological roles played by noncovalent bonds between PARs present on the enzyme and proteins with important functional roles in chromatin (15 16 17 18) . The polymers that are built on 28 sites in the automodification domain of PARP-1 are usually very long, up to 200 ADP-ribose units, and heavily branched (19) . The high number of negative charges on the polymers make them resemble nucleic acids and eventually compete with them.


Figure 1
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  		Figure 1. Poly(ADP-ribosyl)ation. a) Schematic of enzymatic reaction by which PARPs, transferring ADP-ribose from NAD+ to glutamic acid residues on a protein acceptor, allow the formation of ADP-ribose polymers (PARs), whereas PARG is involved in their degradation. b) Schematic shows PARP-1 involved in modifying proteins in the covalent (heteromodification and automodification) and the noncovalent way. The enzyme is the best acceptor of the covalent modification and forms long and branched PARs on its central automodification domain. In this form, PARP-1 can associate with other proteins that interact noncovalently with the enzyme-bound polymers. c) Some of reported regions and the consensus sequence recognized on proteins capable of noncovalent interactions with PARs. CD, catalytic domain; DNA BD, DNA-binding domain; AMD, automodification domain.

Despite the high negative charge, the interaction of PARs with acceptor proteins is nonionic in nature because it does not depend on the basic charge of proteins. Rather, it depends on the presence of a particular consensus amino acid motif, which provides a pocket for noncovalent interactions with PARs (20 , 21) . The typical consensus motif is bipartite and contains 2 conserved regions: a cluster rich in positive residues and the consensus pattern hxbxhhbbhhb, where h indicates residues with hydrophobic side chains; b, a preference for basic amino acid residues; and x, any amino acid residue. Deeper analysis demonstrated that the affinity of the noncovalent PAR interactions with specific acceptor proteins depends on the PAR chain length (22) .


   DNA METHYLATION
TOP
 ABSTRACT
 INTRODUCTION
 PARYLATION
 DNA METHYLATION
CROSSTALK BETWEEN PARYLATION AND...
 CTCF ACTIVATES PARP-1
 CONCLUSIONS
 REFERENCES
 
5-Methylcytosine is considered the fifth base in DNA (added postreplicationally). It expands the genetic information encoded by the sequence of the 4 bases in DNA into the realm of epigenetics because methylation encodes important information on gene expression without altering the genetic information in the DNA (23 , 24) . The DNA methylation pattern is established by the de novo DNA methyltransferase 3a (Dnmt3a) and Dnmt3b methylation enzymes and maintained by the activity of Dnmt1 during replication. Distribution of methylated CpGs on DNA is not random: only 1 to 2% of the genome is unmethylated, with the unmethylated CpGs essentially clustered in promoter regions of housekeeping genes (Fig. 2 ). The unmethylated state of these so-called GpG islands is essential for the expression of the correlated genes. In addition, some repeat sequences are rich in mCpG, and maintaining their methylated state is important for cell functions. Thus, the overall methylation pattern of the genome needs to be maintained for the correct functioning of the cells (23 , 24) . In fact, in tumor cells, the DNA methylation pattern is inverted, because CpG islands are sometimes methylated, and bulk DNA undergoes hypomethylation, with negative consequences for the cell (25 26 27) . Many tumor suppressor genes, whose expression is dependent on the unmethylated state of the CpG islands in their promoters, become down-regulated by increased methylation in these regions (28) ; in contrast, chromatin decondensation (29) , genomic instability (30) , apoptosis (31) , cancer (25 26 27 , 32) , and even mitotic catastrophe (33) can be induced by DNA hypomethylation.


Figure 2
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  		Figure 2. DNA methylation. Schematic shows a chromosome with representative regions rich in CpG dinucleotides whose methylated or unmethylated pattern is required for normal cellular functions. White lollipops, unmethylated CpGs; black lollipops, methylated CpGs.

Although various suggestions have been put forward, the mechanisms by which CpG islands are protected from methylation during replication and in chromatin (23 , 34 35 36) and the mechanisms that introduce widespread hypomethylation in cancer cells are still unknown.


   CROSSTALK BETWEEN PARYLATION AND DNA METHYLATION
TOP
 ABSTRACT
 INTRODUCTION
 PARYLATION
 DNA METHYLATION
 CROSSTALK BETWEEN PARYLATION AND...
CTCF ACTIVATES PARP-1
 CONCLUSIONS
 REFERENCES
 
Over the past decade, our laboratory has accumulated evidence that links PARylation with DNA methylation, suggesting that PARylation regulates gene expression through its control over DNA methylation pattern. A series of various experimental strategies suggests that blockage of PARylation induces in vivo DNA hypermethylation, both in genomic DNA (37 , 38) and in some CpG island regions (39) . These observations suggested that PARs protect DNA from methylation. Further experiments have shown that PARP activity can also affect the methylation pattern of transfected foreign DNA (40) . Recent data (41) reinforce the hypothesis that a physiological level of PARylation and the balance between unmodified and PARylated PARP-1 are crucial in maintaining the genomic methylation pattern. We found that cells with hyperactive PARP-1, and hence increased PAR levels, are characterized by a widespread DNA hypomethylation (41) .

We suggested a mechanism in which PARP-1 in its PARylated form makes Dnmt1 catalytically inactive and thus inefficient in DNA methylation (18) . In this model, modified PARP-1, which is highly negatively charged, outcompetes DNA for binding and hosting Dnmt1. In fact, we found that Dnmt1 is a member of the protein family able to bind long and branched ADP-ribose polymers in a noncovalent way. The enzyme possesses 2 presumptive PAR-binding domains (Fig. 1 ) and shows higher affinity for free polymers than for DNA. PARs, either free or PARP-1 bound, inhibit human recombinant Dnmt1 activity in vitro. Coimmunoprecipitation data indicate that Dnmt1 and PARP-1 associate in vivo and that PARP-1 present in the complex is in its PARylated form (18) .

Figure 3 depicts our model for a possible molecular mechanism through which PARylated PARP-1 is involved in the control of a DNA methylation pattern on genomic DNA. We hypothesize that during normal cell growth, Dnmt1—having a higher affinity for ADP-ribose polymers than for DNA—is associated with PARylated PARP-1, forming PARylated PARP-1/Dnmt1 complex. This interaction precludes Dnmt1 binding to DNA, thus preventing unwanted DNA methylation. The right nuclear balance between the unmodified and the PARylated form of PARP-1, which depends on the correct dynamics of PARPs/PARG activities, determines the maintenance of the DNA methylation pattern. In the absence of PARylated PARP-1, the Dnmt1 is free to methylate DNA, whereas in a condition of persistently high levels of PARylated PARP-1, the stable inhibition of Dnmt1 would prevent its methylation maintenance activity at replicative forks. According to our data, decreased or increased levels of PARylated PARP-1 are responsible for diffuse hypermethylation or hypomethylation of DNA, respectively.


Figure 3
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  		Figure 3. Maintainance of DNA methylation pattern depends on the level of poly(ADP-ribosyl)ation of PARP-1. a) Nuclear level of unmodified and PARylated forms of PARP-1 depends on the correct dynamics of PARPs/PARG activity. b) Decreased or increased levels of PARylated PARP-1 are responsible for diffuse hypermethylation or hypomethylation of DNA, respectively. In the model, polymers present on PARP-1 noncovalently interact with Dnmt1, inhibiting its enzymatic activity. In the absence of PARylated PARP-1, the Dnmt1 is free to methylate DNA, whereas in a condition of persistently high levels of PARylated PARP-1, the stable inhibition of Dnmt1 would prevent its methylation maintenance activity at replicative forks, inducing passive DNA hypomethylation.


   CTCF ACTIVATES PARP-1
TOP
 ABSTRACT
 INTRODUCTION
 PARYLATION
 DNA METHYLATION
 CROSSTALK BETWEEN PARYLATION AND...
 CTCF ACTIVATES PARP-1
CONCLUSIONS
 REFERENCES
 
CTCF, the highly conserved and ubiquitously expressed nuclear factor involved in imprinting and insulator processes (42) , attracted our attention because it brings together the two epigenetic events in which we are interested: DNA methylation and PARylation. As an enhancer-blocking insulator, CTCF interacts with specific sequences located in imprinting control regions, creating loops that physically separate promoters from enhancers to ensure allele-specific control of transcription. Notably, CTCF is able to interact with these regions only if they are unmethylated (43) . Furthermore, CTCF binding protects them from de novo methylation in somatic cells (44 , 45) . Recent studies have linked CTCF function in imprinting control to PARylation of its N-terminal domain (46 , 47) . A PARylated form of CTCF has been found in cells; this form is capable of binding imprinting control regions in vitro. Furthermore, treatment of cells with 3-aminobenzamide, a competitive inhibitor of PARP activity, affects the insulator function of most CTCF target sites.

These results have been interpreted (46) to mean that PARylation of CTCF is responsible for its imprinting function, yet without altering the methylation pattern of the DNA regions involved in the control of imprinting. These are interesting suggestions, albeit not directly supported by the data.

To gain further insight into the mechanism of PARylated CTCF action, we performed a series of in vivo and in vitro experiments (41) . Coimmunoprecipitation and pull-down experiments indicated direct interaction between CTCF and PARP-1. Furthermore, in vitro PARP activity assay demonstrated that CTCF, by itself, activates PARP-1. Importantly, PARP-1 activation occurs even in the absence of "nicked" DNA, which suggests that the CTCF-induced PARP1 activation may not be involved in DNA repair.

We also provided, for the first time, evidence that CTCF is involved in the crosstalk between PARylation and DNA methylation. We found that Dnmt activity is decreased by ~70% in cells overexpressing CTCF vs. cells transfected with an empty vector. A more thorough examination of Dnmt1 indicated that the inhibition is not the result of a decreased protein level. An in vitro approach excluded direct inhibition of Dnmt1 activity by CTCF, which confirmed our previous observation that PARs present on modified PARP-1 inhibit the enzyme (18) . The persistence of high PAR levels induced by CTCF affects the DNA methylation machinery. Dnmt1 activity is inhibited, leading to wide hypomethylation of the genome, which involves both centromeric and B1 repeats (Fig. 4 ). Ectopic overexpression of CTCF in cells that lack PARP-1 demonstrates that the functional relationship between CTCF and PARP-1 is specific. The fact that PARylated PARP-1 inhibits Dnmt1 activity and that CTCF is, by itself, capable of inducing PARylation of PARP-1, allows us to suggest 2 alternative mechanisms to explain the control exerted by PARylation over the expression of imprinted genes (Fig. 5a ). In these models, the inhibition of Dnmt1 activity in cells with active PARylation is attributed to noncovalent interactions between PARs on either PARylated CTCF or PARylated PARP-1 and Dnmt1. Whatever the exact mechanism involved, it is clear that the proper balance between unmodified and PARylated PARP-1 is of paramount importance for, at least in this case, the functioning of gene imprinting.


Figure 4
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  		Figure 4. CTCF activates PARP-1 PARylation, and the PARylated PARP-1 inhibits Dnmt1. Following ectopic overexpression, CTCF induces PARP-1 automodification and poly(ADP-ribosyl)ation of CTCF and of other nuclear proteins yet to be identified. The persistence of PARs in the nuclear environment induces stable inhibition of Dnmt1 activity. Modified PARP-1, binding Dnmt1 noncovalently, inhibits its enzymatic activity, and consequently, the genomic DNA becomes widely hypomethylated.


Figure 5
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  		Figure 5. Two possible mechanisms by which PARP and CTCF are involved in the control of imprinted genes. Models refer to maternally inherited allele of the Igf2/H19 imprinted locus where CTCF binds to the unmethylated imprinting control regions (ICR), creating a chromatin insulator that excludes the Igf2 promoter from the action of downstream enhancers. a) PARylated PARP-1 and/or CTCF preserves the unmethylated state of ICR sequences at the maternally inherited allele by attracting and hosting Dnmt1 through a noncovalent interaction mediated by PARs. In this complex, the Dnmt1 is impeded from gaining access to DNA. The use of inhibitors of poly(ADP-ribosyl)ation reactions depletes CTCF and/or PARP-1 of covalently bound PARs, thus allowing Dnmt1 to escape from the complex and methylate DNA. The right-end schematics depict possible alternative scenarios of interactions at the ICR. b) PARs present on CTCF and/or on PARP-1 are involved in long-range looping interaction between DNA sequences involved in the control of imprinting. PARs present on CTCF or on another protein (e.g., PARP-1) act as noncovalent glue to close the 2 ends of the loop, which ensures the silencing of Igf2 on the maternal allele at the Igf2/H19 locus. Low levels of PARs attained in the presence of PARP inhibitors would lead to loss of imprinting. An alternative possible scenario is depicted on the right.

The discovery of a long-range looping interaction between DNA sequences involved in the control of imprinting and the involvement of CTCF in this interaction (42) suggest another fascinating hypothesis: PARs present on CTCF or on another protein (e.g., PARP-1) act as noncovalent "glue" between the 2 proteins bound at the ends of the loop that ensures the silencing of Igf2 on the maternal allele at the Igf2/H19 locus (Fig. 5b ). Low levels of PARs attained in the presence of PARP inhibitors would lead to loss of imprinting. This scenario, suggested by the presence on the CTCF C-domain of a PAR-interacting domain (Fig. 1 ), raises the possibility that the effect of PARylation on imprinting is independent of Dnmt1 inhibition. The likelihood that PARylation is involved in the regulation of imprinting through both mechanisms cannot be excluded.

It is obvious that despite the clear-cut connection between PARylated PARP-1 and Dnmt1, other additional and/or alternative mechanisms cannot be excluded, because of the complexity of pathways that occur in cells.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 PARYLATION
 DNA METHYLATION
 CROSSTALK BETWEEN PARYLATION AND...
 CTCF ACTIVATES PARP-1
 CONCLUSIONS
REFERENCES
 
Based on our extensive research on PARylation and DNA methylation, we suggest that the control of DNA methylation pattern is among the multiple housekeeping roles of PARP-1. This role could be played by the inhibitory effect exerted by PARs on Dnmt1 (17) . The steady-state levels of PARs present in cells may be extremely important—their decrease causing anomalous DNA hypermethylation (37 38 39 40) but their increase leading to widespread DNA hypomethylation (41) . The control of these patterns is of paramount importance for genome functioning, because DNA methylation constitutes an important part of the epigenetic code. Moreover, we underscore the importance of CTCF in inducing PARP-1 activation, a fact that is especially important in the light of recent genome-wide localization studies that identified thousands of CTCF binding sites in the human genome (49 , 50) .

The unusual cellular environment that results from ectopic overexpression of CTCF, in which large amounts of PARs are present for several days, mimics the situation in PARG knockout cells and provides a model for the study of damage resulting from an excess of polymers in cells. Our data suggest that deregulation of DNA methylation pattern is one of the molecular mechanisms causing lethality in PARG knockout mice (48) .

Findings suggest important research topics to investigate concerning the possibility that 1) the introduction of new methyl groups onto CpG islands of housekeeping genes and/or the diffuse hypomethylation in cancer cells could also occur through deregulation of PARP or PARG activities; 2) the activation of PARP activity dependent on interaction with CTCF is necessary to inhibit the access of Dnmt1 onto the imprinted control regions and to maintain their unmethylated state necessary for the control of imprinting; 3) the activation of PARP activity dependent on interaction with CTCF is also necessary to inhibit the access of Dnmt1 onto other CTCF-binding sequences genome-wide present in human genome; and 4) the lethality observed in PARG knockout mice is the result of a widespread genomic DNA hypomethylation dependent on the excess of PARs.


   ACKNOWLEDGMENTS
 
This work was supported by Ministero Italiano dell’Istruzione, dell’Università e della Ricerca, and by Ministero Italiano della Salute.

Received for publication September 30, 2008. Accepted for publication October 23, 2008.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PARYLATION
 DNA METHYLATION
 CROSSTALK BETWEEN PARYLATION AND...
 CTCF ACTIVATES PARP-1
 CONCLUSIONS
 REFERENCES
 

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