Update on microbe-induced epigenetic changes: bacterial effectors and viral oncoproteins as...

111110.2217/FVL.13.97 © 2013 Future Medicine Ltd ISSN 1746-0794Future Virol. (2013) 8(11), 1111–1126

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Epigenetic regulation in the domains of life

Epigenetic regulation allows a dynamic modula-tion of gene expression by depositing stable but reversible marks on DNA or DNA-associated proteins, and ensures a faithful transmission of gene-expression patterns to each progeny cell upon division (epigenetic memory).

In multicellular organisms of the domain Eukarya, the establishment, maintenance and programmed alterations of cell type-specific gene-expression patterns is controlled by com-plex epigenetic regulatory mechanisms [1–4]. Epigenetic modifications are also widespread in unicellular eukaryotes, and it has been well documented that protozoan pathogens control the expression of virulence genes and differen-tiation-related gene sets by epigenetic regula-tors [1,5–8]. Acquisition of novel genes coding for histone methyltransferase enzymes capable of depositing epigenetic marks on chromatin may facilitate evolutionary transitions. Kishore et al. suggested that horizontal gene transfer events enabled the free-living ancestor of the malaria parasite Plasmodium falciparum and other apicomplexans to alter its lifestyle and

evolve to parasitism, by taking advantage of the more sophisticated epigenetic control of gene expression [9]. They also argued that complex cellular communication and differentiation, the characteristic features of the social amoeba Dictyostelium discoideum that are absent from other amoebae, may also be related to the acqui-sition of a histone methyltransferase gene from animals [9].

Genetically identical unicellular organisms belonging to the domain Bacteria may also gen-erate heritable phenotypic heterogeneity with-out altering the DNA sequence: they use epi-genetic mechanisms to achieve such an adaptive strategy (reviewed in [10]).

Although their physiological function is unknown at present, putative chromatin-mod-ifying enzymes related to certain epigenetic regulators of eukaryotes were also detected in organisms of the domain Archaea [11,12].

Epigenetic regulatory mechanisms: a brief introduction

Epigenetic regulators include DNA meth-yltransferases methylating the C-5 position of cytosines within CpG dinucleotides. In

Update on microbe-induced epigenetic changes: bacterial effectors and viral oncoproteins as epigenetic dysregulators

Hans Helmut Niller1, Ferenc Banati2, Katalin Nagy3, Krisztina Buzas4 & Janos Minarovits*4

1Institute for Medical Microbiology & Hygiene, University of Regensburg, Franz-Josef-Strauss Allee 11, Regensburg D93053, Germany 2RT-Europe Nonprofit Research Center, H-9200 Mosonmagyarovar, Pozsonyi út 88, Hungary 3University of Szeged, Faculty of Dentistry, Department of Oral Surgery, H-6720 Szeged, Tisza Lajos Krt. 64, Hungary 4University of Szeged, Faculty of Dentistry, Department of Oral Biology & Experimental Dental Research, H-6720 Szeged, Tisza Lajos Krt. 64, Hungary *Author for correspondence: Tel.: +36 70 39 48 279 n [email protected]

Pathoepigenetics is a new discipline describing how disturbances in epigenetic regulation alter the epigenotype and gene-expression pattern of human, animal or plant cells. Such ‘epigenetic reprogramming’ may play an important role in the initiation and progression of a wide variety of diseases. Infectious diseases also belong to this category: recent data demonstrated that microbial pathogens, including bacteria and viruses, are capable of dysregulating the epigenetic machinery of their host cell. The resulting heritable changes in host cell gene expression may favor the colonization, growth or spread of infectious pathogens. It may also facil itate the establishment of latency and malignant cell transformation. In this article, we review how bacterial epigenetic effectors and inflammatory processes elicited by bacteria alter the host cell epigenotype, and describe how oncoproteins encoded by human tumor viruses act as epigenetic dysregulators to alter the phenotype and behavior of host cells.

Keywords

n DNA methylation n epigenetic regulation n histone modification n oncovirus n pathoepigenetics n pioneer transcription factor n Polycomb and Trithorax complexes n tumorigenesis

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vertebrates, the control regions of inactive pro-moters are frequently methylated and located to ‘closed’ chromatin domains suppressing transcription (reviewed by [13]). In humans, cytosine methyl ation patterns are maintained by DNA methyltransferase 1 (DNMT1), which has a high affinity to hemimethylated DNA substrates generated during semiconservative DNA replication. DNMT1 restores the meth-ylation pattern of the parental DNA strands on the initially unmethylated daughter strands. Maintenance DNA methyltransferases are tar-geted to replication foci by interacting with PCNA and UHRF1; alternatively, they could also be recruited by a series of transcription factors [14–18].

De novo DNA methyltransferases (DNMT3A, and DNMT3B in humans) are involved in the establishment of DNA methylation pat-terns during embryonic development. They act preferentially on completely unmethyl-ated DNA strands. In addition, by anchoring strongly to nucleosomes in highly methylated regions of the genome [19], they also contrib-ute, paradoxically, to the maintenance of DNA methylation, by de novo methylating the sites missed by DNMT1 in densely methylated heterochromatin domains [20,21].

Cytosine methylation is reversible; it can be removed by active or passive ‘eraser’ mecha-nisms. The Tet family of dioxygenases converts 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine fol-lowed by base excision repair (active demethyl-ation; reviewed in [22]). Passive demethylation may occur when the recruitment of mainte-nance DNA methyltransferase DNMT1 is inef-ficient or the activity of the enzyme is inhibited during DNA replication (reviewed in [23]).

In addition to DNA methylation, covalent modifications of core histone molecules, the principal components of the nucleosome, also constitute epigenetic marks that influence the structure and accessibility of chromatin as well as promoter activity. Mitotically heritable his-tone marks are typically deposited by histone acetylases, protein arginine methyltransferases and histone lysine methyltransferases. The lat-ter enzymes may also act as components of Polycomb (PcG) and Trithorax group (TrxG) multiprotein complexes (reviewed in [3]). It is important to note that certain TrxG and PcG proteins not only covalently modify histones, but also remain associated with mitotic chro-matin and influence the activity of neighboring promoters in postmitotic cells [24,25].

Similar to DNA methylation, histone modifi-cations are reversible: they are removed by his-tone deacetylases, histone lysine demethylases or the histone arginine demethylase JMJD6 [26,27]. It is noteworthy that both demethylation of lysine and active demethylation of cytosine depend on oxygenases (reviewed in [2]). Thus, Jeltsch argued that the major reversible epigen-etic systems could possibly appear only in the Cambrian period, after an increase in atmo-spheric oxygen. Jeltsch suggested that such a change could have been a precondition for the generation of different classes of oxygenases, the enzymes permitting the use of stable but reversible covalent chromatin modifications for gene regulation, a key factor in the evolution of multicellular organisms [2].

Epigenetic marks determine chromatin struc-ture and accessibility by interacting with ‘reader’ factors, including methylcytosine (mC) binding proteins, transcription factors and chromatin remodeling complexes, which affect and regu-late transcription [3]. Active promoters are usu-ally located to domains of open chromatin or euchromatin, whereas silent promoters are typi-cally situated in closed, condensed chromatin domains or heterochromatin.

In addition to covalently modified tails of core histones, certain histone variants may also convey epigenetic information. The histone variant H2A.Z marked transcriptional start sites of active genes in mitotic chromosomes, changed nucleosome occupancy and permitted promoter activation after chromosome decon-densation. Based on these observations, Kelly et al. and Kelly and Jones speculated that altered nucleosome occupancy may form a novel epigen-etic mechanism [28,29]. It is worthy to note that histone chaperones play an important role in nucleosome assembly (reviewed in [30]), as well as in the regulation of histone modifications [31–33].

Direct binding of distinct nonhistone pro-teins to regulatory regions of the genome may also constitute epigenetic marks that can be inherited to daughter cells. So-called ‘pio-neer’ transcription factors or ‘bookmarking’ proteins remain bound to chromatin even in mitotic chromosomes, and accelerate transcrip-tional reactivation following mitosis. They are capable of binding to highly methylated DNA sequences, opening up chromatin through the replacement of linker histone H1, and induc-ing cytosine demethylation. Pioneer transcrip-tion factors binding to tissue-specific enhancers precedes transcriptional activation of the genes associated with such premarked enhancers [34].

Review Niller, Banati, Nagy, Buzas & Minarovits

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In addition to DNA methylation, histone modifications, histone variants and bookmark-ing proteins, long noncoding RNA (lncRNA) molecules are also potential carriers of epigen-etic information. They may directly interact with PRC2 and target the activity of the his-tone lysine methyltransferase EZH2 to selected genomic loci, resulting in trimethylation of histone H3 at lysine 27 (H3K27me3), chro-matin condensation and promoter silencing. LncRNAs also interact with other chromatin remodeling complexes (reviewed in [35]).

DNA methylation and histone modifications may spread from their primary sites of deposi-tion to neighboring chromatin areas, resulting in the establishment of extended heterochro-matic or euchromatic regions; that is, nuclear subcompartments repressing or facilitating transcription, respectively (reviewed in [36,37]). Long-distance chromatin interactions mediated by CTCF (CCCTC binding factor) and cohe-sin proteins may insulate chromatin domains and allow coregulation of promoters within the loops by preventing the spread of chroma-tin modifications from adjacent areas. Certain chromatin loops may be preserved in mitotic chromosomes and could possibly contribute to epigenetic memory [38].

Microbe-induced pathoepigenetic changes

By now, it has become a well-established fact that disturbances in epigenetic regulation play an important role, not only in tumorigenesis [39], but also in the development of a variety of human, animal and plant diseases. Thus, recently a new discipline was born, patho-epigenetics, which describes the pathologic changes elicited by epigenetic dysregulation [40], as summarized in two newly published books [41,42]. The chapters in these books clearly dem-onstrate that disturbances in various epigenetic processes may alter the epigenotype of cells, and that such epigenetic reprogramming may mani-fest in pathological changes, disease initiation and progression.

It has also been recognized that microbial pathogens could dysregulate epigenetic mecha-nisms in host cells (reviewed in [8,40,43]). As far as we know, HIV, the causative agent of AIDS, was the first human pathogen associated with the induction of pathoepigenetic alterations in host cells [44].

In the second part of this article, we briefly summarize recent results regarding the role of epigenetic pathways in pathologic processes

associated with bacterial infections, and out-line how epigenetic ideas have changed basic concepts in the field of virus-induced neoplasms.

Epigenetic alterations induced by bacteria in host cellsEpigenetic alterations of eukaryotic genomic DNA induced by bacterial infection of host cells or infected tissue have received more atten-tion in recent years. A spectrum of bacteria as diverse as Listeria monocytogenes, Streptococcus pneumoniae, Clostridium perfringens, Aeromonas hydrophila, Porphyromonas gingivalis, Shigella flexneri, Anaplasma phagocytophilum, Myco-bacterium tuberculosis, Chlamydia trachomatis, Chlamydia pneumoniae, Campylobacter rectus, uropathogenic Escherichia coli (UPEC) and Helicobacter pylori have been demonstrated to interfere with the epigenetic machinery of the host cell. This was comprehensively reviewed in 2012 [8,45,46]. Therefore, here we will focus on a few examples of above list as well as some pathogenic bacterial species that have recently been added to this ever growing list: Mycobacte-rium leprae, Legionella pneumophila, Bordetella bronchiseptica and Burkholderia thailandensis [47]. In short, pathogenic bacteria may perma-nently alter the epigenotype of host cells – either directly through introducing bacterial products into the host tissue or indirectly by eliciting a chronic inflammatory response. Bacterial epi-genetic effectors may be injected into target cells, or may be produced intracellularly and induce localized chromatin alterations, thereby inhibit-ing the expression of specific immune defenses or tumor suppressor genes. The sustained sup-pression of immune and tumor suppressor genes may result in a difficult-to-overcome chronic inflammation and malignant transformation of the affected tissue, which may be – especially in the case of H. pylori – foreshadowed by an epigenetic field for cancerization [48].

One of the best studied examples of bacterial interference with cellular epigenetic machin-ery is in Listeria monocytogenes. Listeriolysin produced by L. monocytogenes and a group of related bacterial toxins produced by S. pneu-moniae (pneumolysin), C. perfringens (perfrin-golysin) and A. hydrophila (aerolysin) belong to a class of secreted, cholesterol-dependent and pore-forming cytolysins (reviewed in [49]). Liste-riolysin enables Listeria to evade the phagosome and, upon infection, initially downregulate the immune response through modification of the histone code of a specific set of immune genes [50]. The efflux of K+ through membrane pore

Bacterial effectors & viral oncoproteins as epigenetic dysregulators Review


formation seems to play a major signaling role for the transcriptional reprogramming of the immune genes [51]. LntA, another listerial viru-lence factor, targets the vertebrate heterochro-matinization protein BAHD1, which is involved in the repression of interferon-stimulated genes (ISGs) in epithelial cells [52]. When LntA is switched on during the listerial infection cycle, ISGs become induced through the de-repression of BAHD1-containing silencing complexes by LntA [53]. This Listeria-controlled expression of ISGs may contribute to control the listerial colonization of the host [45].

Another well-studied example is P. gingi-valis, which interferes with the human epi-genetic machinery through the secretion of butyrate, an HDAC inhibitor, and thereby causes periodontal disease and may be associ-ated with an adverse pregnancy outcome [54]. In human periodontal ligament fibroblast cell culture, P. gingivalis lipopolysaccharide (LPS) led to the strong induction of DNMT1, which in turn led to hypermethylation of the gene for transcription factor RUNX2. The inter-ference of P. gingivalis with the cellular epi-genetic machinery may be the cause for the inhibition of osteoblastic differentiation in the periodontium [55]. By contrast, in keratinocyte cell culture, DNMT1, DNMT3a and JMJD3 gene expression was downregulated by expo-sure to LPS. Gingival fibroblasts from patients with periodontal disease or healthy individuals showed no downregulation of those three genes in this study [56]. In HIV-infected patients with periodontal disease, the high amount of P. gingivalis-secreted butyrate in the periodontal pockets may be instrumental in reactivating and disseminating latent HIV through the de-repression of HDAC-containing complexes on the LTR of integrated proviruses [57,58].

A. phagocytophilum, a tick-transmitted, oblig-atory intracellular rickettsial pathogen, is capa-ble of survival in the hostile intra cellular envi-ronment inside granulocytes and monocytes. This is accomplished through the downregula-tion of cellular defense genes through the bac-terial effector AnkA. AnkA increases HDAC1 expression and targets it to several defense gene promoters, thereby repressing them [59,60] (reviewed in [61]).

L. pneumophila is the causative agent of Legionnnaire’s disease, a life-threatening type of pneumonia. Smoking, alcohol consumption and older age increase the risk of acquiring the disease when exposed to the bacterium, usually by using a shower that has bacterially

contaminated water pipes. L. pneumophila infects and replicates within free-living amoe-bae and alveolar macrophages, and contains a type IV secretion system, which among other effectors targets a SET-domain protein to the nucleoli of infected lung cells. This Legionella SET domain effector, called LegAS4, is a his-tone lysine methyltransferase (HKMTase), which specifically activates the transcription of rDNA. The activation of rDNA transcription is mediated through direct contact with hetero-chromatin proteins (HP)1a and -g, and subse-quent H3K4me methylation. Other pathogenic bacteria – B. bronchiseptica and B. thailanden-sis – contain analogous SET-domain proteins that are targeted to the host nucleolus and also induce rDNA transcription [47]. Li et al. pro-pose that increased rDNA transcription may be a general bacterial virulence strategy, which helps the bacterium to survive in the harsh intracellular environment [47]. Another type IV secreted SET-domain protein of L. pneu-mophila, RomA, was shown to repress host cell gene expression through H3K14me3 methyla-tion and decreased H3K14 acetylation [62]. In L. pneumophila-infected cultured lung epithe-lial cells, genome-wide histone modifications and increased IL-8 expression were observed. The induction of IL-8 expression was due to H4 acetylation, H3 acetylation and H3 phos-phorylation and was dependent on the bacterial flagellins [63] (reviewed in [45]).

UPEC strains are well adapted to the colo-nization of uro-epithelia. Besides other mecha-nisms, this is achieved through the epigeneti-cally mediated and strongly upregulated expres-sion of siderophores compared with the prior life of E. coli in the gut [64]. This resembles the quick epigenetic alterations of bacterial genomes in M. avium spp. paratuberculosis in bovines upon their change of habitat [65]. UPEC-infected uroepithelial cultured cells internalized bacterial colonies and strongly upregulated DNMT1 and, in parallel, down-regulated the expression of the tumor sup-pressor gene CDKN2A. The DNA repair gene MGMT was also downregulated (however, not by DNA methylation), while a set of control tumor suppressor genes was unaffected, indicat-ing a targeted DNA-methylation mechanism. Internalization of bacteria was dependent on the bacterial FimH gene [66] (reviewed in [67,68]).

H. pylori infection is the strongest risk factor for developing gastric carcinoma. Intermedi-ate steps before contracting a astric carcinoma are chronic inf lammation, gastric atrophy,



metaplasia and dysplasia. Vacuolating cyto-toxin and cytotoxicity-associated antigen are major virulence factors. Coculture of H. pylori with mouse macrophages led to TLR4-medi-ated induction of IL-6 expression, which was caused by NF-kB and MAPK signaling [69]. The chronic inflammation process is accom-panied by alterations of the histone code and by extensive alterations of DNA methylation. Global hypomethylation and local hyper-methylation at CpG islands of tumor sup-pressor gene loci is strongly associated with the presence of H. pylori in chronic gastritis and with progression to cancer (reviewed in [8,46,70]). Recently, the promoter of the forkhead box gene, FOXD3, was found to be increas-ingly methylated and thereby silenced during the progression of H. pylori-associated gastric tumors in both humans and mice. The expres-sion of FoxD3-dependent genes for cell death regulators CYFIP2 and RARB was correspond-ingly decreased [71]. In an animal model, cancer was prevented in H. pylori-infected gerbils that were treated with 5-aza-dC, a DNA-demethyl-ating agent. This again confirms that epigene-tic disruption induced by H. pylori is an impor-tant mechanism in the generation of gastric cancer [72]. The relative importance of chronic inflammation in H. pylori-induced carcinogen-esis remains to be clarified. It is clear that in an animal model chronic gastric inflammation triggered by H. pylori contributes greatly to carcinogenesis [73]. Niwa et al. conducted ger-bil infection experiments and found increasing DNA methylation at ten selected CpG islands for the duration of the gastric inflammation [73]. H. pylori eradication led to a recovery of the normal methylation status. However, under immune suppression with cyclospo-rine A, when the inflammatory response was blocked, they did not observe increased DNA methylation in infected gerbils. The authors concluded that the epigenetic disruption was mostly caused by chronic inflammation, but not by the infection itself [73]. While there is a strong case for inflammation, examples of a direct H. pylori effect on epigenetic alterations have been reviewed in Chiariotti et al. [70]. The quantitative significance of direct epigenetic disruption by H. pylori effectors remains to be analyzed.

Mycobacterium tuberculosis is the causative agent of tuberculosis, an infectious disease mostly affecting the lungs, although all other organs may be affected. Immune control of M. tuberculosis is mostly cell mediated, with

a requirement for IFN-g secretion to activate macrophages, as only activated macrophages are able to kill off intracellular mycobacteria. In monocyte co-culture M. tuberculosis blocked IFN-g-mediated induction of a series of MHC class II genes. The inhibition was dependent on HDAC and involved a silencing complex at the respective promoters [74]. Pennini et al. were able to show that this chromatin remod-eling effect was caused by M. tuberculosis 19K lipoprotein (LpqH) signaling via TLR2 [75,76]. Comparing the methylation statuses of CpG islands in the vitamin D receptor gene has uncovered variations at several CpG dinucleo-tides between different ethnic groups and between M. tuberculosis-infected and -unin-fected individuals [77]. It may be interesting to speculate whether a person’s CpG-methylation profile may be predictive for M. tuberculo-sis susceptibility, or whether different CpG-methylation profiles may have been induced by M. tuberculosis infection. This is certainly an interesting field for further research (reviewed in [78]). However, as a note of caution, methyla-tion analyses were performed from EBV-trans-formed lymphoblastoid cell lines obtained from the respective donors [77]. EBV by itself may contribute to an altered methylation profile in the host cell [79].

Leprosy, or Hansen’s disease, which has been in existence since biblical times, is caused by M. leprae, another member of the mycobacte-ria family. Fortunately, worldwide incidence rates are decreasing. Intriguingly, M. leprae infection of Schwann cells derived from adult mouse peripheral nerves led to a fundamental reprogramming of those cells. Reprogramming resembled epithelial–mesenchymal transition and involved the epigenetic downregulation of differentiation-associated genes, upregula-tion of mesoderm developmental genes, and imparted plasticity, migratory and immuno-modulatory behavior to the cells. The new progenitor/stem-like cell phenotype promoted the dissemination of the infection. A compre-hensive set of mesodermal and differentiation genes was compared between Schwann cells and progenitor/stem-like cell for their meth-ylation status, and significant differences were shown according to the cellular phenotype [80].

The abovementioned examples demonstrate clearly that epigenetic disruption elicited by chronic bacterial infection causes long-lasting effects. Analogously, acute infection may also provoke epigenetic disruption with long-lasting consequences, especially when the infection is



severe; for example, bacterial sepsis. A charac-teristic systemic inflammatory response syn-drome, caused by the liberation of too high an amount of cytokines and the accompanying dysregulation of normally tightly regulated sys-tems, such as coagulation, blood pressure and organ perfusion, is usually induced by septice-mic infection. Systemic inflammatory response syndrome may be balanced by compensatory anti-inflammatory response syndrome in order to survive the acute impact, but compensa-tory anti-inf lammatory response syndrome may leave the survivor of sepsis with profound postseptic immune suppression, which confers a high susceptibility to opportunistic infec-tions that may last for weeks or even years (reviewed in [81,82]). Post-septic immune sup-pression correlates with tolerance to bacterial LPS (synonymous with endotoxin) and clearly has an epigenetic basis. Both the histone code and the DNA methylation status of the TNF-a promoter are altered in cultured LPS-tolerant human monocytes. TNF-a gene expression is suppressed by a silencing complex on its promoter, which contains the histone methyl-transferases G9a, HP1 and DNMT3a/b [83]. During LPS tolerance of cultured monocytes, I-kBa expression was sustained dependent on RelB, which was mirrored in peripheral blood leukocytes [84] (reviewed in [45]). TLR4 signal-ing during bacterial infection induced HDAC SIRT1, which accumulated at the TNF-a and IL-1b promoters, but not at the I-kB pro-moter, thereby silencing TNF-a and IL-1b, and establishing endotoxin tolerance. The results from the cultured monocyte cell line experiment were again reflected by comparing peripheral blood leukocytes from septic patients and healthy control patients [85]. Accordingly, in gingival tissue biopsies from patients with severe chronic periodontal disease, the pro-moter of the TNF-a gene was downregulated by methylation at two CpG dinucleotides [86]. Therefore, evidence is slowly accumulating for the long-lasting effects of severe acute infection, which are mediated by the epigenetic disrup-tion of immune response genes. It is tempting to speculate that some hematological diseases, for example, subgroups of myelodysplastic syn-drome, which occurs with an overall incidence of <5/100.000 per year, but up to 40/100.000 per year among the elderly, may be a conse-quence of a postinfectious epigenetic disruption leading to a permanent dysregulation of specific genes, which in some cases cannot be balanced out during a person’s lifetime [87].

Epigenetic reprogramming in oncovirus-associated neoplasmsFor a long period of time, genetic theories domi-nated the field of cancer research. Step by step it became clear, however, that in addition to genetic changes including mutations, deletions, gene amplifications and chromosomal altera-tions, epigenetic reprogramming also plays an important role in tumorigenic processes [88]. All of the major classes of cancer-causing agents – including bacteria, chemical carcinogens, hormones, metals, radiation and viruses – elicit epigenetic alterations, and epigenetic changes occur both in preblastomatoses and in all sub-sequent stages of tumorigenesis and neoplastic progression (see section ‘Epigenetic alterations induced by bacteria in host cells’, and [89]).

Regarding human tumor viruses, initial stud-ies focused mainly on the interactions of viral oncoproteins with cellular regulatory proteins controlling cell proliferation and apoptosis, and there have been substantial efforts to map the batteries of cellular genes switched on or off by viral oncoproteins and study cell type-dependent expression of the viral oncogenes in tumor biopsies, tumor-derived cell lines and transfected cells [90,91]. However, by now it has also been well documented that oncoproteins encoded by human tumor viruses alter the epigenotype of cells.

Epstein–Barr virusEpigenetic changes frequently occur in virus-associated human neoplasms. The viral onco-proteins HPV E7, EBV LMP1, KSHV LANA, HCV core protein and HBV HBx upregulate or stimulate the activity of at least one DNA methyltransferase enzyme, resulting in hyper-methylation and silencing of certain cellular promoters (Tables 1 & 2; reviewed in [43,46,92]). The modulation of DNMT levels may depend, however, on the phenotype of the host cell. We shall illustrate this point using the example of EBV, a herpesvirus associated with a series of malignant tumors. LMP1, a latent membrane protein encoded by EBV, is expressed both in certain B-cell lymphoma types and in EBV-associated carcinomas (reviewed in [93]). It was observed that LMP1 increased the level of DNMT1, DNMT3A and DNMT3B in epithelial cells, including nasopharyngeal car-cinoma cells, via c-Jun NH

2-terminal kinase

signaling [94–96]. However, LMP1 upregulated only DNMT3A in germinal center B cells, in parallel with downregulation of DNMT1 and DNMT3B [97], and similar changes in DNMT



levels were observed in cell lines of germinal center B-cell-derived, EBV-positive Hodgkin’s lymphomas. One may speculate that cell type-specific expression of transcription factors or epigenetic regulators may affect individual DNA MTase levels and influence the changes of the epigenome in epithelial and germinal center B cells carrying latent EBV episomes. In EBV-infected gastric carcinoma cells that do not express the LMP1 oncoprotein, another viral protein, LMP2A, induced the phosphory-lation of STAT3, a protein that binds to the promoter of the DNMT1 gene [98]. As a con-sequence, DNMT1 was upregulated, resulting in hypermethylation of the PTEN tumor sup-pressor gene promoter. In one gastric carcinoma cell line upregulation of DNMT3B was also

observed [98]. Thus, the very same DNA tumor virus may induce CpG methylation-mediated promoter silencing via the expression of distinct oncoproteins – LMP1 or LMP2A.

Latent EBV genomes carry cell type-depen-dent epigenetic marks, and these viral epig-enotypes determine the host cell-dependent gene-expression patterns of the viral episomes [99]. Hughes et al. raised the point that elevated levels of cellular DNA methyltransferases may contribute to the establishment and mainte-nance of latency type I, characterized by the expression of a single viral protein, the nuclear antigen EBNA1 [100]. Contrary to their expec-tations, however, shRNA expression plasmid-mediated knockdown of DNMT1, DNMT3B or both DNA methyltransferases in latency

Table 1. Epigenetic alterations induced by oncoproteins of DNA viruses in human cells

Virus Viral protein Epigenetic mechanism or regulator affected Outcome or expected outcome

EBV EBNA1 Maintenance of DNA methylationBookmarking

HypomethylationGene activation (?)

EBNA2 Histone acetylation Promoter activation

EBNA3A (EBNA3) PRC2 (recruitment) Promoter silencing

EBNA3C (EBNA6) PRC2 (recruitment) Promoter silencing

LP (EBNA5) HDAC4 (displacement) Coactivation

LMP1 DNMT1, DNMT3A, DNMT3B (upregulation)PRC1 (Bmi-I; upregulation)KDM3A (downregulation; targets H3K9me2)KDM6B (induction; demethylation of H3K27me3)

Promoter silencingPromoter silencing and activationPromoter silencingPromoter activation

LMP2A DNMT1, DNMT3B (upregulation) Promoter silencing

KSHV LANA DNMT1, DNMT3A, DNMT3B (recruitment to cellular promoters)MeCP2 (association)HP1 (association)Histone deacetylases (association)Brd2/RING3 (binding, induction, relocation)

Promoter silencingPromoter silencing and activationTargetingPromoter silencingInhibits formation of heterochromatin

HBV HBx DNMT1, DNMT3A (upregulation)DNMT3B (downregulation)

Promoter silencingHypomethylation of repetitive sequences

HDV Delta antigen DNMT3B (upregulation) Promoter silencing

HPV E7 DNMT1 (upregulation)Histone acetyltransferases (upregulation)H3K27me3 demethylases (induction)

Promoter silencingPromoter activationPromoter activation

Table 2. Epigenetic alterations induced by oncoproteins of RNA viruses in human cells.

Virus Viral protein Epigenetic mechanism or regulator affected Outcome or expected outcome

HCV Core protein DNMT1, DNMT3B (upregulation) Promoter silencing

HTLV-I Tax Arginine methyltransferaseHistone acetyltransferases (binding)Nap1 (histone chaperone)histone deacetylase HDAC1 (recruitment)

Promoter activationPromoter activationNucleosome disassemblyPromoter silencing

HBZ Histone acetyltransferases (binding in a ternary complex)Histone acetyltransferases (binding, direct inhibition)

Promoter activationPromoter silencing



type I Burkitt’s lymphoma cell lines failed to induce a change in latency type or EBV latency promoter usage, indicating that these DNA methyltransferases are dispensable for the main-tenance of EBV latency type I. Hughes et al. also investigated whether the chromatin bound-ary factor CTCF (CCCTC-binding factor), an insulator protein capable of stabilizing chroma-tin loops, was involved in the maintenance or establishment of strict type I EBV latency. This was a most interesting study in light of recent chromatin conformation data suggesting that CTCF-mediated alternative loop formation might regulate the usage of alternative latency promoters Qp (latency type I, EBNA1 only) and Cp (latency type III, six EBNAs expressed) [101]. Hughes et al. observed that knockdown of CTCF failed to induce a switch from latency type I to latency type III, indicating that it was dispensable for the maintenance of strict latency. They noticed, however, that deletion of a CTCF binding site located in the vicinity of Cp, the activated B-cell-specific EBV promoter, permitted a prolonged, low level of Cp activity in one of the two superinfected latency type I BL cell lines, although EBNA2, a marker of

latency type III, could not be detected. They concluded that in this in vitro model of EBV latency, CTCF might contribute to Cp silencing [100]. By contrast, Salamon et al., using in vivo footprinting, chromatin immunoprecipitation and high-resolution methylation analysis, did not find a correlation between CTCF bind-ing and Cp activity in EBV-carrying cell lines [102]. Based on these observations, Takacs et al. speculated that CTCF may play a structural role, that is, it may contribute to structural 3D organization of EBV episomes [103]. An analy-sis of EBV episomes by chromatin immunopre-cipitation followed by deep sequencing revealed that in the BL line Raji 15 CTCF binding sites are spread over the viral genome. Six of those CTCF binding sites colocalized with binding sites for the cohesin subunit Rad21, which may stabilize chromatin loops in concert with CTCF (Figure 1) [104]. Holdorf et al. argued that the observed CTCF occupancy near both active and repressed promoters would be compatible with a context-dependent role for CTCF in gene regulation [104]. We think, however, that their data are also compatible with a structural role for CTCF. Thus, in concert with other proteins,

LMP2Ap

LMP1 LMP2BLRS

TR FR DS Rep*

Cp

oriP

Qp

EBER1 & 2Wp

BHLF1

BOLF1BMRF1BLRF1BZLF1BGLF1BDLF1

BVRF1

BILF2

RPMS1

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+ +CTCF

RPB1

RAD21

Figure 1. Binding of CTCF, cohesin and RNA polymerase II to the latent EBV genome in the Burkitt’s lymphoma cell line Raji. The EBV genome is depicted as a circular episome generated by the fusion of the linear dsDNA genome at the TR after infection of a B cell. The positions of the binding sites for CTCF, RAD21 (a component of cohesin) and RPB1 (a subunit of RNA polymerase II) were determined by Holdorf et al. [104], and are indicated by the symbols shown in the figure. The LRS governs the transcription of the LMP1 and LMP2B genes encoding latent membrane proteins. LMP2A transcripts coding for a similar transmembrane protein are initiated at an independent promoter. Solid black arrows show the positions of viral promoters; letters and numbers adjacent to them indicate the open reading frames of viral proteins. Dashed arrows emanating from oriP indicate the long range enhancer activity of oriP, the latent origin of EBV replication. EBER1 and 2 are transcription units for nontranslated RNAs. FR and DS denote sequences within oriP (family of repeats and a dyad symmetry element). Rep* is a sequence implicated in latent EBV replication. Cp, Wp and Qp are alternative promoters for the transcripts of EBNAs. EBNA: EBV nuclear antigen; LRS: LMP1 regulatory sequence; TR: Terminal repeat.



CTCF may contribute to the chromatin looping function of the locus control region of the EBV genome [101,105,106] or have a function other than the control of EBV gene expression, such as tar-geting of EBV episomes to distinct chromatin domains within the nucleus [107].

In addition to the upregulation of DNA methyltransferases, EBV LMP1 also elevates the level of the PRC1 protein Bmi-1. Bmi-1 silences certain cellular promoters, but simul-taneously activates other target genes that have been implicated in leukemogenesis [108].

The nuclear proteins EBNA3A and EBNA3C also affect polycomb proteins: they recruit PRC2, which inactivates a target promoter by increased histone H3 lysine 27 trimethylation [109].

In germinal center B cells, the viral onco-protein LMP1 induced KDM6B, an ‘eraser’ enzyme demethylating histone H3K27me3, a typical mark of heterochromatin [110]. The NF-kB signaling pathway, mediating several LMP1-elicited changes in gene expression, was not involved in KDM6B upregulation. A battery of genes targeted by KDM6B was also found to be upregulated during germinal center B-cell differentiation and in Hodgkin’s lymphoma, suggesting a role for EBV-induced epigenetic reprogramming in lymphomagenesis [110].

EBV LMP1 and LMP2A upregulate the miRNA miR-155 that targets the 3´ untrans-lated region of the mRNA encoding KDM3A, resulting in a downregulation of KDM3A in nasopharyngeal carcinoma cells [111]. A decreased level of the ‘eraser’ enzyme is expected to result in an increased level of the repres-sive chromatin mark H3K9me2 at a subset of silenced promoters.

We note that the nuclear proteins EBNA1, EBNA2 and EBNA-LP (EBNA5) also interact with the epigenetic machinery, favoring euchro-matin formation. EBNA1 may elicit site-spe-cific demethylation at its binding sites [112] and, similarly to pioneer transcription factors, it may mark cellular genes for activation [113]. EBNA2, the major transactivator protein of EBV, binds histone acetyltransferases, whereas EBNA-LP (EBNA5) acts as a coactivator by displacing histone deacetylase from promoters [114,115].

KSHVLANA, the latency-associated nuclear antigen of KSHV (the causative agent of Kaposi’s sar-coma and two B lymphocyte disorders), forms a complex with the H3K9 histone demethylase KDM3A, recruiting it to distinct sites of the

viral episome [116]. In latently infected cells abla-tion of KDM3A expression inhibits the expres-sion of viral genes, implying a regulatory role for LANA in the transcription of the KSHV genome by recruiting KDM3A that may prevent the deposition of or may erase a heterochromatic histone mark, H3K9me2.

How gene silencing and activating mecha-nisms are targeted in virus-transformed cells remains to be established. It is interesting to note, however, that KSHV LANA is capable of recruiting a de novo DNA methyltransferase to cellular promoters [117]. In addition, KSHV LANA, by its interaction with the methyl-cytosine binding protein MeCP2, may repress or activate genes in a context-dependent manner [118]. It is also noteworthy that KSHV LANA binds to, induces and relocates the chromatin-binding protein Brd2/RING3 [119,120]. Such an interaction may contribute to the inhibition of heterochromatin formation in the neighbor-hood of cellular chromatin-associated KSHV episomes (reviewed in [43]).

HBV & hepatitis delta virusHBV is one of the causative agents of hepa-tocellular carcinoma. The epigenetic changes of HBV-induced liver cancers have recently been reviewed in [121]. It is noteworthy that in hepatocellular carcinoma cells, HBx, the HBV-encoded pleiotropic regulator protein, upregu-lated the DNA methyltransferases DNMT1, DNMT3A1 and DNMT3A2 [122]. As a conse-quence, a set of target genes, including tumor suppressor genes, became hypermethylated. In contrast, HBx downregulated DNMT3B, the enzyme involved in the de novo methylation of satellite repeats (Table 1) [122] (reviewed in [43,46]). Prevention of repetitive DNA methylation by HBx may contribute to the establishment of a typical methylation pattern frequently observed in neoplasms of nonviral etiology: overall hypo-methylation and focal hypermethylation of the tumor cell genome, compared with its normal counterpart [39].

Hepatitis delta virus (HDV) is a subviral sat-ellite RNA virus that replicates only in the pres-ence of a helper hepadnavirus, which is HBV in humans [123]. For this reason, HDV has not been considered as an oncovirus, although it enhances the development of liver cirrhosis and hepatocellular carcinoma in HBV-infected indi-viduals. Benegiamo et al. found that the HDV-encoded delta antigen upregulated DNMT3B in a human hepatoma cell line via activation of the STAT3 pathway [124]. Upregulation of



DNMT3B was accompanied by increased methylation of the E2F1 promoter and G2/M cell cycle arrest. The effect of HDV delta anti-gen on the methylation of satellite repeats or other repetitive sequences was not investigated. Benegiamo et al. speculated that in HBV- and HDV-infected hepatocytes, escape mutations allow the cells to counteract delta antigen-induced cell cycle arrest, resulting in cells with altered cell cycle regulation [124].

HCVHCV, one of the causative agents of hepatocel-lular carcinoma, is the only human oncovirus that replicates exclusively in the cytoplasm. The ssRNA genome of HCV is not known to be reverse transcribed in human cells, and unlike retroviral RNA genomes, it does not produce a DNA copy capable of integration into the host cell genome (reviewed in [125]). The epigenetic signatures associated with HCV infection have recently been reviewed [121]. We would like to emphasize that the HCV core protein is capable of upregulating DNMT1 and DNMT3B, and induces hypermethylation of the E-cadherin promoter, resulting in downregulation of the E-cadherin level and an increased invasion ability of core protein-expressing cells [126,127]. Ripoli et al. reported that in Huh-7 hepatoma cells, the expression of genotype 1b HCV core protein did not affect the methylation pattern of other cellular genes, including GSTP1, APC, TIMP3 and CNNTB1, but induced SIRT1 [127]. SIRT1 functions as a NAD-dependent histone deacetylase, but it is also capable of deacetylating nonhistone proteins (reviewed in [128]). One may speculate that SIRT1 contributed to the HCV core protein-induced silencing of the E-cad-herin promoter because treatment with sirtinol, an inhibitor of SIRT1, increased E-cadherin mRNA expression and decreased E-cadherin promoter methylation [127].

HPVHPVs are the causative agents of cervical car-cinoma [129]. The E7 oncoprotein of HPV was initially characterized as a direct inhibitor of the tumor suppressor protein Rb, a regulator of the cell cycle (reviewed in [130]). The very same interaction has epigenetic consequences as well: Holland et al. demonstrated that E2F, the cellular binding partner of Rb, was released from its binding pocket in E7 protein-express-ing cells and induced the EZH2 gene, coding for the histone methyltransferase EZH2 [131]. Upregulation of the PRC2 component EZH2

did not, however, result in an expected increase of the epigenetic mark histone H3K27me3 in foreskin keratinocytes expressing the HPV16 oncoproteins E6 and E7, because the corre-sponding demethylase enzyme, KDM6A, was upregulated in parallel [132]. In addition, the PRC1 protein BMI1 was downregulated in E6 and E7- expressing cells. Thus, complex epi-genetic changes may contribute to an increased proliferation capacity and apoptosis resistance of HPV-positive cervical carcinoma cells [131] (reviewed in [133]). In HPV-positive head and neck squamous cell carcinoma (HNSCC) sam-ples, Lechner et al. observed hypermethylation of PRC2 target genes, including cadherin genes [134]. Ectopic expression of E6 and E7 proteins in a HNSCC cell line partly recapitulated the HPV-specif ic DNA methylation signature observed in HPV-associated neoplasms. Lechner et al. suggested that in the HNSCC cell line, the main effector mediating the alteration of the host cell methylome was HPV E6 [134].

However, HPV has a dual effect on the cel-lular epigenotype. Whereas promoter silenc-ing is possibly achieved by the upregulation of DNMT1, promoter activation may occur via his-tone acetyltransferases and histone H3K27me3 demethylases [135] (reviewed in [43]).

Human T-lymphotropic virus Type ITax is a promiscuous transactivator oncoprotein encoded by a retrovirus, human T-lymphotropic virus Type I (HTLV-I), the causative agent of adult T-cell leukemia/lymphoma [136]. Tax has also been characterized as an inhibitor of the tumor suppressor Rb – it associates with Rb and targets Rb for proteasomal degradation [137].

Tax acts upon its recognition sequences located in the proviral long terminal repeat and activates a series of cellular genes, including c-onc genes and genes encoding growth factors via different transcriptional pathways (reviewed in [136,138–140]). It is noteworthy that Tax binds both to histone acetyltransferases and to PRMT4 (also called CARM1), which act coop-eratively in coactivator complexes (reviewed in [141,142]). At Tax-activated (HTLV-I) promot-ers, histone acetylation by cellular coactivators was followed by acetylation-dependent eviction of the entire histone octamer, a process medi-ated by the histone chaperone Nap1. Thus, a nucleosome-free promoter region, a signature of transcriptionally active genes, was established [142]. Tax has a negative effect on the expres-sion of a set of cellular genes. One of its targets is SHP-1, a gene coding for a candidate tumor



suppressor protein, SH2 homology-containing protein-tyrosine phosphatase 1 [143]. Tax recruits a histone deacetylase, HDAC1, to the SHP-1 promoter, resulting in the displacement of the transcription factor NF-kB.

Tax expression is frequently lost in aggressive forms of ATL due to hypermethylation of the HTLV-I promoter. However, the expression of HTLV-I bZIP factor (HBZ; a basic leucine zipper domain protein), which is encoded by the minus strand of the provirus, is not lost even at the late stages of ATL (reviewed in [144]). Similarly to Tax, HBZ is involved both in the activation and repression of transcription. HBZ forms a ternary complex with the coactivator p300, which also carries histone acetyl transferase activity, and SMAD3, a mediator of TGF-b signaling [144]. In naive mouse T cells, HBZ enhanced the tran-scription of a battery of cellular genes, includ-ing the gene for the pioneer transcription factor Foxp3. Foxp3 in mice and the corresponding FOXP3 in humans is a master regulator of Treg cell development: it determines the cell type-spe-cific epigenotype, gene-expression pattern and cellular identity (reviewed in [145]). Zhao et al. speculated that in HTLV-I-infected individuals, HBZ-induced FOXP3 may convert the infected T cells into Treg cells. Such a conversion may explain the suppressive effect exerted by ATL cells on bystander CD4+ cells [144].

Tax and HBZ have frequently shown opposite effects on cellular gene expression. Tax represses whereas HBZ activates transcription of DKK1, a gene coding for the Dickkopf-1 protein that inhibits osteoblast differentiation and facilitates bone resorption [146]. Polakowski et al. suggested that during the late stages of ATL when Tax expression is switched off, HBZ may upregulate DKK1, contributing to the development of lytic bone lesions. Although the coactivator p300/CBP was indispensable for DKK1 activation by HBZ, the very same research group also reported direct inhibition of p300/CBP-associated ace-tyl transferase activity [147]. One my speculate that HTLV-I infection, via complex effects of HBZ, may reduce overall levels of acetylated his-tones in parallel with context-dependent local increases in HAT activity.

Future perspectiveResearch in the field of microbe induced patho-epigenetic alterations has apparently intensified in recent years. In this review we focused exclu-sively on human pathogens, although epigenetic dysregulation caused by microbial infections is also an important topic in veterinary medicine

[8], and epigenetic mechanisms are known to affect plant–pathogen interactions [148].

We did not deal with protozoan parasites, which have their own sophisticated epigenetic regulatory systems controlling, among others, the expression of virulence genes and differenti-ation-related genes [8]. We expect that novel data will accumulate in the near future regarding the pathoepigenetic effects of protozoan parasites infecting humans and animals, as the epigenetic machinery of unicellular parasites may interfere with the epigenetic control system of their hosts. It is noteworthy that epigenetic drugs targeting Plasmodium falciparum histone lysine methyl-transferases and a histone acetyltransferase inhibitor could arrest parasite growth [149,150].

We noticed that most research efforts in the field of bacterial pathoepigenetics concentrated on obligate intracellular or facultative intra-cellular pathogens and chronic bacterial infec-tions. We expect that the field will broaden and epigenetic research will extend to other impor-tant bacterial pathogens as well. Regarding viral pathogens, we highlighted recent results on human oncoviruses only, although other viruses not involved directly in tumorigenesis also induce epigenetic alterations. In addition to chronic viral infections, viruses that do not persist in their hosts for a long period may also leave epigenetic marks on certain cells of the host organisms.

Because epigenetic changes are reversible, elucidation of epigenetic pathways involved in microbial diseases may open the way to the elaboration of novel, epigenetic therapies. One of the potential applications is the use of epi-genetic drugs to attempt curative treatment of HIV-infected individuals and AIDS patients. The idea is to activate dormant HIV proviruses using epigenetic therapy that may kill the reac-tivated cells and apply intensified HAART in parallel to curb the spread of the virus (reviewed in [151]). Another possibility is targeted epigenetic silencing of HIV transcription to help HAART in blocking HIV replication [151].

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the sub-ject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.



References1. Aravind L, Abhiman S, Iyer LM. Natural

history of the eukaryotic chromatin protein methylation system. Prog. Mol. Biol. Transl. Sci. 101, 105–176 (2011).

2. Jeltsch A. Oxygen, epigenetic signaling, and the evolution of early life. Trends Biochem. Sci. 38(4), 172–176 (2013).

3. Jin B, Li Y, Robertson KD. DNA methylation: superior or subordinate in the epigenetic hierarchy? Genes Cancer. 2(6), 607–617 (2011).

4. Jurkowski TP, Jeltsch A. On the evolutionary origin of eukaryotic DNA methyltransferases and Dnmt2. PLoS ONE 6(11), e28104 (2011).

5. Coyne RS, Lhuillier-Akakpo M, Duharcourt S. RNA-guided DNA rearrangements in ciliates: is the best genome defence a good offence? Biol. Cell 104(6), 309–325 (2012).

6. Fisk JC, Read LK. Protein arginine methylation in parasitic protozoa. Eukaryot. Cell 10(8), 1013–1022 (2011).

7. Hoeijmakers WA, Stunnenberg HG, Bartfai R. Placing the Plasmodium falciparum epigenome on the map. Trends Parasitol. 28(11), 486–495 (2012).

8. Niller HH, Banati F, Ay E, Minarovits J. Microbe-induced epigenetic alterations. In: Patho-Epigenetics of Disease. Minarovits J, Niller HH (Eds). Springer, NY, USA, 419–455 (2012)

9. Kishore SP, Stiller JW, Deitsch KW. Horizontal gene transfer of epigenetic machinery and evolution of parasitism in the malaria parasite Plasmodium falciparum and other apicomplexans. BMC Evol. Biol. 13, 37 (2013).

10. Casadesus J, Low DA. Programmed heterogeneity: epigenetic mechanisms in bacteria. J. Biol. Chem. 288(20), 13929–13935 (2013).

11. Manzur KL, Zhou MM. An archaeal SET domain protein exhibits distinct lysine methyltransferase activity towards DNA-associated protein MC1-alpha. FEBS Lett. 579(17), 3859–3865 (2005).

12. Niu Y, Xia Y, Wang S et al. A prototypic lysine methyltransferase 4 from archaea with degenerate sequence specificity methylates chromatin proteins Sul7d and Cren7 in different patterns. J. Biol. Chem. 288(19), 13728–13740 (2013).

13. Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene 20(24), 3139–3155 (2001).

14. Araujo FD, Croteau S, Slack AD et al. The DNMT1 target recognition domain resides in the N terminus. J. Biol. Chem. 276(10), 6930–6936 (2001).

15. Hervouet E, Lalier L, Debien E et al. Disruption of Dnmt1/PCNA/UHRF1 interactions promotes tumorigenesis from human and mice glial cells. PLoS ONE 5(6), e11333 (2010).

16. Hervouet E, Nadaradjane A, Gueguen M, Vallette FM, Cartron PF. Kinetics of DNA methylation inheritance by the Dnmt1-including complexes during the cell cycle. Cell Div. 7, 5 (2012).

17. Iida T, Suetake I, Tajima S et al. PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA. Genes Cells 7(10), 997–1007 (2002).

18. Spada F, Haemmer A, Kuch D et al. DNMT1 but not its interaction with the replication machinery is required for maintenance of DNA methylation in human cells. J. Cell Biol. 176(5), 565–571 (2007).

19. Jeong S, Liang G, Sharma S et al. Selective anchoring of DNA methyltransferases 3A and 3B to nucleosomes containing methylated DNA. Mol. Cell Biol. 29(19), 5366–5376 (2009).

20. Jones PA, Liang G. Rethinking how DNA methylation patterns are maintained. Nat. Rev. Genet. 10(11), 805–811 (2009).

21. Gatto S, D’Esposito M, Matarazzo MR. The role of DNMT3B mutations in the pathogenesis of ICF syndrome. In: Patho-Epigenetics of Disease. Minarovits J, Niller HH (Eds). Springer, NY, USA, 15–41 (2012).

22. Wu H, Zhang Y. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev. 25(23), 2436–2452 (2011).

23. Smith ZD, Meissner A. The simplest explanation: passive DNA demethylation in PGCs. EMBO J. 32(3), 318–321 (2013).

24. Aoto T, Saitoh N, Sakamoto Y, Watanabe S, Nakao M. Polycomb group protein-associated chromatin is reproduced in post-mitotic G1 phase and is required for S phase progression. J. Biol. Chem. 283(27), 18905–18915 (2008).

25. Blobel GA, Kadauke S, Wang E et al. A reconfigured pattern of MLL occupancy within mitotic chromatin promotes rapid transcriptional reactivation following mitotic exit. Mol. Cell. 36(6), 970–983 (2009).

26. Cloos PA, Christensen J, Agger K, Helin K. Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev. 22(9), 1115–1140 (2008).

27. Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat. Rev. Genet. 10(1), 32–42 (2009).

28. Kelly TK, Miranda TB, Liang G et al. H2A.Z maintenance during mitosis reveals nucleosome shifting on mitotically silenced genes. Mol. Cell. 39(6), 901–911 (2010).

29. Kelly TK, Jones PA. Role of nucleosomes in mitotic bookmarking. Cell Cycle. 10(3), 370–371 (2011).

Executive summary

Microbe-induced pathoepigenetic changes�n Pathoepigenetic mechanisms play an important role in the initiation and progression of both rare and common human diseases,

including diseases associated with bacterial and viral infections.

Epigenetic alterations induced by bacteria in host cells�n Pathogenic bacteria, such as Porphyromonas gingivalis, Helicobacter pylori, Mycobacterium leprae and others may permanently alter

the epigenotype of host cells directly through bacterial products or indirectly by eliciting a chronic inflammatory response.

Epigenetic reprogramming in oncovirus-associated neoplasms�n In contrast to bacterial epigenetic effectors, none of the oncoproteins encoded by human tumor viruses code for a histone

methyltransferase.�n The viral oncoproteins HPV E7, EBV LMP1, KSHV LANA, HCV core protein and HBV HBx upregulate or stimulate the activity of at least

one DNA methyltransferase enzyme, resulting in hypermethylation and the silencing of certain cellular promoters.�n The EBV nuclear antigens, KSHV LANA and HPV E7, and HTLV-I oncoproteins Tax and HBZ interact with a series of additional epigenetic

modifier proteins as well.



30. Burgess RJ, Zhang Z. Histone chaperones in nucleosome assembly and human disease. Nat. Struct. Mol. Biol. 20(1), 14–22 (2013).

31. Begum NA, Stanlie A, Nakata M, Akiyama H, Honjo T. The histone chaperone Spt6 is required for activation-induced cytidine deaminase target determination through H3K4me3 regulation. J. Biol. Chem. 287(39), 32415–32429 (2012).

32. Stevenson JS, Liu H. Nucleosome assembly factors CAF-1 and HIR modulate epigenetic switching frequencies in an H3K56 acetylation-associated manner in Candida albicans. Eukaryot. Cell 12(4), 591–603 (2013).

33. Wang AH, Zare H, Mousavi K et al. The histone chaperone Spt6 coordinates histone H3K27 demethylation and myogenesis. EMBO J. 32(8), 1075–1086 (2013).

34. Zaret KS, Watts J, Xu J, Wandzioch E, Smale ST, Sekiya T. Pioneer factors, genetic competence, and inductive signaling: programming liver and pancreas progenitors from the endoderm. Cold Spring Harb. Symp. Quant. Biol. 73, 119–126 (2008).

35. Nie L, Wu HJ, Hsu JM et al. Long non-coding RNAs: versatile master regulators of gene expression and crucial players in cancer. Am. J. Transl. Res. 4(2), 127–150 (2012).

36. Doerfler W. The impact of foreign DNA integration on tumor biology and evolution via epigenetic alterations. In: Patho-Epigenetics of Disease. Minarovits J, Niller HH (Eds). Springer, NY, USA, 14–378 (2012).

37. Gyory I, Minarovits J. Epigenetic regulation of lymphoid specific gene sets. Biochem. Cell Biol. 83(3), 286–295 (2005).

38. Burke LJ, Zhang R, Bartkuhn M et al. CTCF binding and higher order chromatin structure of the H19 locus are maintained in mitotic chromatin. EMBO J. 24(18), 3291–3300 (2005).

39. Jones PA, Baylin SB. The epigenomics of cancer. Cell 128(4), 683–692 (2007).

40. Minarovits J. Microbe-induced epigenetic alterations in host cells: the coming era of patho-epigenetics of microbial infections. A review. Acta Microbiol. Immunol. Hung. 56(1), 1–19 (2009).

41. Minarovits J, Niller HH. Patho-Epigenetics of Disease. Minarovits J, Niller HH (Eds). Springer, NY, USA (2012).

42. Tollefsbol TO. Epigenetics in Human Disease. Tollefsbol TO (Ed.). Academic Press, MA, USA (2012).

43. Niller HH, Banati F, Ay E, Minarovits J. Epigenetic changes in virus-associated neoplasms. In: Patho-Epigenetics of Disease. Minarovits J, Niller HH (Eds). Springer, NY, USA, 179–225 (2012).

44. Mikovits JA, Young HA, Vertino P et al. Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-gamma) promoter and subsequent downregulation of IFN-gamma production. Mol. Cell Biol. 18(9), 5166–5177 (1998).

45. Bierne H, Hamon M, Cossart P. Epigenetics and bacterial infections. Cold Spring Harb. Perspect. Med. 2(12), a010272 (2012).

46. Niller HH, Minarovits J. Epigenetics and human infectious diseases. In: Epigenetics in Human Disease. Tollefsbol TO (Ed.). Academic Press, MA, USA, 415–442 (2012).

47. Li T, Lu Q, Wang G et al. SET-domain bacterial effectors target heterochromatin protein 1 to activate host rDNA transcription. EMBO Rep. 14(8), 733–740 (2013).

48. Ushijima T. Epigenetic field for cancerization. J. Biochem. Mol. Biol. 40(2), 142–150 (2007).

49. Hamon M, Bierne H, Cossart P. Listeria monocytogenes: a multifaceted model. Nat. Rev. Microbiol. 4(6), 423–434 (2006).

50. Hamon MA, Batsche E, Regnault B et al. Histone modifications induced by a family of bacterial toxins. Proc. Natl Acad. Sci. USA 104(33), 13467–13472 (2007).

51. Hamon MA, Cossart P. K+ efflux is required for histone H3 dephosphorylation by Listeria monocytogenes listeriolysin O and other pore-forming toxins. Infect. Immun. 79(7), 2839–2846 (2011).

52. Bierne H, Tham TN, Batsche E et al. Human BAHD1 promotes heterochromatic gene silencing. Proc. Natl Acad. Sci. USA 106(33), 13826–13831 (2009).

53. Lebreton A, Lakisic G, Job V et al. A bacterial protein targets the BAHD1 chromatin complex to stimulate type III interferon response. Science 331(6022), 1319–1321 (2011).

54. Darveau RP. The oral microbial consortium’s interaction with the periodontal innate defense system. DNA Cell Biol. 28(8), 389–395 (2009).

55. Uehara O, Abiko Y, Saitoh M, Miyakawa H, Nakazawa F. Lipopolysaccharide extracted from Porphyromonas gingivalis induces DNA hypermethylation of runt-related transcription factor 2 in human periodontal fibroblasts. J.Microbiol.Immunol.Infect. doi:10.1016/j.jmii.2012.08.005 (2012) (Epub ahead of print).

56. de Camargo Pereira G, Guimaraes GN, Planello AC et al. Porphyromonas gingivalis LPS stimulation downregulates DNMT1, DNMT3a, and JMJD3 gene expression levels in human HaCaT keratinocytes. Clin. Oral Investig. 17(4), 1279–1285 (2013).

57. Imai K, Ochiai K, Okamoto T. Reactivation of latent HIV-1 infection by the periodontopathic bacterium Porphyromonas gingivalis involves histone modification. J. Immunol. 182(6), 3688–3695 (2009).

58. Imai K, Ochiai K. Role of histone modification on transcriptional regulation and HIV-1 gene expression: possible mechanisms of periodontal diseases in AIDS progression. J. Oral Sci. 53(1), 1–13 (2011).

59. Garcia-Garcia JC, Barat NC, Trembley SJ, Dumler JS. Epigenetic silencing of host cell defense genes enhances intracellular survival of the rickettsial pathogen Anaplasma phagocytophilum. PLoS Pathog. 5(6), e1000488 (2009).

60. Garcia-Garcia JC, Rennoll-Bankert KE, Pelly S, Milstone AM, Dumler JS. Silencing of host cell CYBB gene expression by the nuclear effector AnkA of the intracellular pathogen Anaplasma phagocytophilum. Infect. Immun. 77(6), 2385–2391 (2009).

61. Rennoll-Bankert KE, Dumler JS. Lessons from Anaplasma phagocytophilum: chromatin remodeling by bacterial effectors. Infect. Disord. Drug Targets 12(5), 380–387 (2012).

62. Rolando M, Sanulli S, Rusniok C et al. Legionella pneumophila effector RomA uniquely modifies host chromatin to repress gene expression and promote intracellular bacterial replication. Cell Host. Microbe. 13(4), 395–405 (2013).

63. Schmeck B, Lorenz J, N’guessan PD et al. Histone acetylation and flagellin are essential for Legionella pneumophila-induced cytokine expression. J. Immunol. 181(2), 940–947 (2008).

64. Henderson JP, Crowley JR, Pinkner JS et al. Quantitative metabolomics reveals an epigenetic blueprint for iron acquisition in uropathogenic Escherichia coli. PLoS Pathog. 5(2), e1000305 (2009).

65. O’Shea B, Khare S, Klein P et al. Amplified fragment length polymorphism reveals specific epigenetic distinctions between Mycobacterium avium subspecies paratuberculosis isolates of various isolation types. J. Clin. Microbiol. 49(6), 2222–2229 (2011).

66. Tolg C, Sabha N, Cortese R et al. Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells. Lab. Invest. 91(6), 825–836 (2011).

67. Tolg C, Bagli DJ. Uropathogenic Escherichia coli infection: potential importance of epigenetics. Epigenomics. 4(2), 229–235 (2012).

68. Schulz WA. Uropathogenic bacteria leave a mark. Lab. Invest. 91(6), 816–818 (2011).



69. Pathak SK, Basu S, Bhattacharyya A et al. TLR4-dependent NF-kappaB activation and mitogen- and stress-activated protein kinase 1-triggered phosphorylation events are central to Helicobacter pylori peptidyl prolyl cis-, trans-isomerase (HP0175)-mediated induction of IL-6 release from macrophages. J. Immunol. 177(11), 7950–7958 (2006).

70. Chiariotti L, Angrisano T, Keller S et al. Epigenetic modifications induced by Helicobacter pylori infection through a direct microbe-gastric epithelial cells cross-talk. Med.Microbiol.Immunol. 202(5), 327–337 (2013).

71. Cheng AS, Li MS, Kang W et al. Helicobacter pylori causes epigenetic dysregulation of FOXD3 to promote gastric carcinogenesis. Gastroenterology 144(1), 122–133 (2013).

72. Niwa T, Toyoda T, Tsukamoto T, Mori A, Tatematsu M, Ushijima T. Prevention of Helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent. Cancer Prev. Res. (Phila.) 6(4), 263–270 (2013).

73. Niwa T, Tsukamoto T, Toyoda T et al. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res. 70(4), 1430–1440 (2010).

74. Wang Y, Curry HM, Zwilling BS, Lafuse WP. Mycobacteria inhibition of IFN-gamma induced HLA-DR gene expression by up-regulating histone deacetylation at the promoter region in human THP-1 monocytic cells. J. Immunol. 174(9), 5687–5694 (2005).

75. Pennini ME, Pai RK, Schultz DC, Boom WH, Harding CV. Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-gamma-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling. J. Immunol. 176(7), 4323–4330 (2006).

76. Pennini ME, Liu Y, Yang J, Croniger CM, Boom WH, Harding CV. CCAAT/enhancer-binding protein beta and delta binding to CIITA promoters is associated with the inhibition of CIITA expression in response to Mycobacterium tuberculosis 19-kDa lipoprotein. J. Immunol. 179(10), 6910–6918 (2007).

77. Andraos C, Koorsen G, Knight JC, Bornman L. Vitamin D receptor gene methylation is associated with ethnicity, tuberculosis, and TaqI polymorphism. Hum. Immunol. 72(3), 262–268 (2011).

78. Esterhuyse MM, Linhart HG, Kaufmann SH. Can the battle against tuberculosis gain from epigenetic research? Trends Microbiol. 20(5), 220–226 (2012).

79. Niller HH, Wolf H, Minarovits J. Epigenetic dysregulation of the host cell genome in Epstein–Barr virus-associated neoplasia. Semin. Cancer Biol. 19(3), 158–164 (2009).

80. Masaki T, Qu J, Cholewa-Waclaw J, Burr K, Raaum R, Rambukkana A. Reprogramming adult Schwann cells to stem cell-like cells by leprosy bacilli promotes dissemination of infection. Cell 152(1–2), 51–67 (2013).

81. Carson WF, Cavassani KA, Dou Y, Kunkel SL. Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics 6(3), 273–283 (2011).

82. McCall CE, Yoza B, Liu T, El Gazzar M. Gene-specific epigenetic regulation in serious infections with systemic inflammation. J. Innate. Immun. 2(5), 395–405 (2010).

83. El Gazzar M, Yoza BK, Chen X, Hu J, Hawkins GA, McCall CE. G9a and HP1 couple histone and DNA methylation to TNFalpha transcription silencing during endotoxin tolerance. J. Biol. Chem. 283(47), 32198–32208 (2008).

84. Chen X, Yoza BK, El Gazzar M, Hu JY, Cousart SL, McCall CE. RelB sustains IkappaBalpha expression during endotoxin tolerance. Clin. Vaccine Immunol. 16(1), 104–110 (2009).

85. Liu TF, Yoza BK, El Gazzar M, Vachharajani VT, McCall CE. NAD+-dependent SIRT1 deacetylase participates in epigenetic reprogramming during endotoxin tolerance. J. Biol. Chem. 286(11), 9856–9864 (2011).

86. Zhang S, Barros SP, Moretti AJ et al. Epigenetic regulation of TNFA expression in periodontal disease. J. Periodontol. doi:10.1902/jop.2013.120294 (2013) (Epub ahead of print).

87. Niller HH. Myelodysplastic syndrome (MDS) as a late stage of subclinical hemophagocytic lymphohistiocytosis (HLH): a putative role for Leptospira infection. A hypothesis. Acta Microbiol. Immunol. Hung. 57(3), 181–189 (2010).

88. Munoz P, Iliou MS, Esteller M. Epigenetic alterations involved in cancer stem cell reprogramming. Mol. Oncol. 6(6), 620–636 (2012).

89. Minarovits J, Niller HH. Patho-epigenetics. Med. Epigenetics 1(1), 37–45 (2013).

90. Javier RT, Butel JS. The history of tumor virology. Cancer Res. 68(19), 7693–7706 (2008).

91. Pagano JS, Blaser M, Buendia MA et al. Infectious agents and cancer: criteria for a causal relation. Semin. Cancer Biol. 14(6), 453–471 (2004).

92. Poreba E, Broniarczyk JK, Gozdzicka-Jozefiak A. Epigenetic mechanisms in virus-induced tumorigenesis. Clin. Epigenetics. 2(2), 233–247 (2011).

93. Liebowitz D. Epstein–Barr virus pathogenesis. In: Human Tumor Viruses.

McCance DJ (Ed.). ASM Press, Washington, DC, USA, 175–199 (1998).

94. Seo SY, Kim EO, Jang KL. Epstein–Barr virus latent membrane protein 1 suppresses the growth-inhibitory effect of retinoic acid by inhibiting retinoic acid receptor-beta2 expression via DNA methylation. Cancer Lett. 270(1), 66–76 (2008).

95. Tsai CL, Li HP, Lu YJ et al. Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(

2)-terminal kinase

signaling. Cancer Res. 66(24), 11668–11676 (2006).

96. Tsai CN, Tsai CL, Tse KP, Chang HY, Chang YS. The Epstein–Barr virus oncogene product, latent membrane protein 1, induces the downregulation of E-cadherin gene expression via activation of DNA methyltransferases. Proc. Natl Acad. Sci .USA 99(15), 10084–10089 (2002).

97. Leonard S, Wei W, Anderton J et al. Epigenetic and transcriptional changes which follow Epstein–Barr virus infection of germinal center B cells and their relevance to the pathogenesis of Hodgkin’s lymphoma. J. Virol. 85(18), 9568–9577 (2011).

98. Hino R, Uozaki H, Murakami N et al. Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Cancer Res. 69(7), 2766–2774 (2009).

99. Minarovits J. Epigenotypes of latent herpesvirus genomes. Curr. Top. Microbiol. Immunol. 310, 61–80 (2006).

100. Hughes DJ, Marendy EM, Dickerson CA, Yetming KD, Sample CE, Sample JT. Contributions of CTCF and DNA methyltransferases DNMT1 and DNMT3B to Epstein–Barr virus restricted latency. J. Virol. 86(2), 1034–1045 (2012).

101. Tempera I, Klichinsky M, Lieberman PM. EBV latency types adopt alternative chromatin conformations. PLoS Pathog. 7(7), e1002180 (2011).

102. Salamon D, Banati F, Koroknai A et al. Binding of CCCTC-binding factor in vivo to the region located between Rep* and C-promoter of Epstein–Barr virus is unaffected by CpG methylation and does not correlate with Cp activity. J. Gen. Virol. 90(Pt 5), 1183–1189 (2009).

103. Takacs M, Banati F, Koroknai A et al. Epigenetic regulation of latent Epstein–Barr virus promoters. Biochim. Biophys. Acta 1799(3–4), 228–235 (2010).

104. Holdorf MM, Cooper SB, Yamamoto KR, Miranda JJ. Occupancy of chromatin organizers in the Epstein–Barr virus genome. Virology 415(1), 1–5 (2011).



105. Zetterberg H, Borestrom C, Nilsson T, Rymo L. Multiple EBNA1-binding sites within oriPl are required for EBNA1-dependent transactivation of the Epstein–Barr virus C promoter. Int. J. Oncol. 25(3), 693–696 (2004).

106. Niller HH, Salamon D, Banati F, Schwarzmann F, Wolf H, Minarovits J. The LCR of EBV makes Burkitt’s lymphoma endemic. Trends Microbiol. 12(11), 495–499 (2004).

107. Nayyar VK, Shire K, Frappier L. Mitotic chromosome interactions of Epstein–Barr nuclear antigen 1 (EBNA1) and human EBNA1-binding protein 2 (EBP2). J. Cell Sci. 122(Pt 23), 4341–4350 (2009).

108. Dutton A, Woodman CB, Chukwuma MB et al. Bmi-1 is induced by the Epstein–Barr virus oncogene LMP1 and regulates the expression of viral target genes in Hodgkin lymphoma cells. Blood 109(6), 2597–2603 (2007).

109. Paschos K, Parker GA, Watanatanasup E, White RE, Allday MJ. BIM promoter directly targeted by EBNA3C in polycomb-mediated repression by EBV. Nucleic Acids Res. 40(15), 7233–7246 (2012).

110. Anderton JA, Bose S, Vockerodt M et al. The H3K27me3 demethylase, KDM6B, is induced by Epstein–Barr virus and over-expressed in Hodgkin’s lymphoma. Oncogene 30(17), 2037–2043 (2011).

111. Du ZM, Hu LF, Wang HY et al. Upregulation of MiR-155 in nasopharyngeal carcinoma is partly driven by LMP1 and LMP2A and downregulates a negative prognostic marker JMJD1A. PLoS ONE 6(4), e19137 (2011).

112. Lin IG, Tomzynski TJ, Ou Q, Hsieh CL. Modulation of DNA binding protein affinity directly affects target site demethylation. Mol. Cell Biol. 20(7), 2343–2349 (2000).

113. Niller HH, Minarovits J. Similarities between the Epstein–Barr virus (EBV) nuclear protein EBNA1 and the pioneer transcription factor FoxA: is EBNA1 a ‘bookmarking’ oncoprotein that alters the host cell epigenotype? Pathogens 1, 37–51 (2012).

114. Portal D, Rosendorff A, Kieff E. Epstein–Barr nuclear antigen leader protein coactivates transcription through interaction with histone deacetylase 4. Proc. Natl Acad. Sci. USA 103(51), 19278–19283 (2006).

115. Wang L, Grossman SR, Kieff E. Epstein–Barr virus nuclear protein 2 interacts with p300, CBP, and PCAF histone acetyltransferases in activation of the LMP1 promoter. Proc. Natl Acad. Sci. USA 97(1), 430–435 (2000).

116. Kim KY, Huerta SB, Izumiya C et al. Kaposi’s sarcoma-associated herpesvirus (KSHV)

latency-associated nuclear antigen regulates the KSHV epigenome by association with the histone demethylase KDM3A. J. Virol. 87(12), 6782–6793 (2013).

117. Shamay M, Krithivas A, Zhang J, Hayward SD. Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi’s sarcoma-associated herpesvirus LANA. Proc. Natl Acad. Sci. USA 103(39), 14554–14559 (2006).

118. Stuber G, Mattsson K, Flaberg E et al. HHV-8 encoded LANA-1 alters the higher organization of the cell nucleus. Mol. Cancer. 6, 28 (2007).

119. Mattsson K, Kiss C, Platt GM et al. Latent nuclear antigen of Kaposi’s sarcoma herpesvirus/human herpesvirus-8 induces and relocates RING3 to nuclear heterochromatin regions. J. Gen. Virol. 83(Pt 1), 179–188 (2002).

120. Viejo-Borbolla A, Ottinger M, Bruning E et al. Brd2/RING3 interacts with a chromatin-binding domain in the Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen 1 (LANA-1) that is required for multiple functions of LANA-1. J. Virol. 79(21), 13618–13629 (2005).

121. Herceg Z, Paliwal A. Epigenetic mechanisms in hepatocellular carcinoma: how environmental factors influence the epigenome. Mutat. Res. 727(3), 55–61 (2011).

122. Park IY, Sohn BH, Yu E et al. Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology 132(4), 1476–1494 (2007).

123. van Regenmortel MHV, Fauquet CM, Bishop DHL et al. Virus taxonomy. In: The Classification and Nomenclature of Viruses. Seventh Report of the International Committee on Taxonomy of Viruses (ICTV). van Regenmortel MHV, Fauquet CM, Bishop DHL et al. (Eds). Academic Press, MA, USA (2000).

124. Benegiamo G, Vinciguerra M, Guarnieri V, Niro GA, Andriulli A, Pazienza V. Hepatitis delta virus induces specific DNA methylation processes in Huh-7 liver cancer cells. FEBS Lett. 587(9), 1424–1428 (2013).

125. Wong DK, Walker BD. Hepatitis C virus. In: Human Tumor Viruses. McCance DJ (Ed.). ASM Press, MA, USA, 301–329 (1998)

126. Arora P, Kim EO, Jung JK, Jang KL. Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b. Cancer Lett. 261(2), 244–252 (2008).

127. Ripoli M, Barbano R, Balsamo T et al. Hypermethylated levels of E-cadherin promoter in Huh-7 cells expressing the HCV

core protein. Virus Res. 160(1–2), 74–81 (2011).

128. Stunkel W, Campbell RM. Sirtuin 1 (SIRT1): the misunderstood HDAC. J. Biomol. Screen. 16(10), 1153–1169 (2011).

129. zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat. Rev. Cancer 2(5), 342–350 (2002).

130. Nead MA, McCance DJ. Activities of the transforming proteins of human papillomaviruses. In: Human tumor viruses. McCance DJ (Ed.). ASM Press, MA, USA, 225–251 (1998)

131. Holland D, Hoppe-Seyler K, Schuller B et al. Activation of the enhancer of zeste homologue 2 gene by the human papillomavirus E7 oncoprotein. Cancer Res. 68(23), 9964–9972 (2008).

132. Hyland PL, McDade SS, McCloskey R et al. Evidence for alteration of EZH2, BMI1, and KDM6A and epigenetic reprogramming in human papillomavirus Type 16 E6/E7-expressing keratinocytes. J. Virol. 85(21), 10999–11006 (2011).

133. Szalmas A, Konya J. Epigenetic alterations in cervical carcinogenesis. Semin. Cancer Biol. 19(3), 144–152 (2009).

134. Lechner M, Fenton T, West J et al. Identification and functional validation of HPV-mediated hypermethylation in head and neck squamous cell carcinoma. Genome Med. 5(2), 15 (2013).

135. McLaughlin-Drubin ME, Crum CP, Munger K. Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming. Proc. Natl Acad. Sci. USA 108(5), 2130–2135 (2011).

136. Newman CL, Rosenblatt JD. Human T-cell lymphotropic viruses. In: Human Tumor Viruses. McCance D (Ed.). ASM Press, Washington, DC, USA, 331–357 (1998)

137. Kehn K, Fuente CL, Strouss K et al. The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation. Oncogene 24(4), 525–540 (2005).

138. Cheng H, Ren T, Sun SC. New insight into the oncogenic mechanism of the retroviral oncoprotein Tax. Protein Cell. 3(8), 581–589 (2012).

139. Ishikawa C, Kawakami H, Uchihara JN, Senba M, Mori N. CD69 overexpression by human T-cell leukemia virus type 1 Tax transactivation. Biochim. Biophys. Acta 1833(6), 1542–1552 (2013).

140. Nakachi S, Nakazato T, Ishikawa C et al. Human T-cell leukemia virus type 1 tax transactivates the matrix metalloproteinase 7 gene via JunD/AP-1 signaling. Biochim. Biophys. Acta 1813(5), 731–741 (2011).



141. Jeong SJ, Lu H, Cho WK, Park HU, Pise-Masison C, Brady JN. Coactivator-associated arginine methyltransferase 1 enhances transcriptional activity of the human T-cell lymphotropic virus type 1 long terminal repeat through direct interaction with Tax. J. Virol. 80(20), 10036–10044 (2006).

142. Nyborg JK, Egan D, Sharma N. The HTLV-1 Tax protein: revealing mechanisms of transcriptional activation through histone acetylation and nucleosome disassembly. Biochim. Biophys. Acta 1799(3–4), 266–274 (2010).

143. Cheng J, Kydd AR, Nakase K et al. Negative regulation of the SH2-homology containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein. Blood 110(6), 2110–2120 (2007).

144. Zhao T, Matsuoka M. HBZ and its roles in HTLV-1 oncogenesis. Front. Microbiol. 3, 247 (2012).

145. Ay E, Buzas K, Banati F, Minarovits J. Recent results in the development of fetal immune system: self, epigenetic regulation, fetal immune responses. In: Maternal Fetal Transmission Of Human Viruses And Their Influence On Tumorigenesis. Berencsi G (Ed.). Springer, NY, USA, 51–82 (2012).

146. Polakowski N, Gregory H, Mesnard JM, Lemasson I. Expression of a protein involved in bone resorption, Dkk1, is activated by HTLV-1 bZIP factor through its activation domain. Retrovirology 7, 61 (2010).

147. Wurm T, Wright DG, Polakowski N, Mesnard JM, Lemasson I. The HTLV-1-encoded protein HBZ directly inhibits the acetyl transferase activity of p300/CBP. Nucleic Acids Res. 40(13), 5910–5925 (2012).

148. Holeski LM, Jander G, Agrawal AA. Transgenerational defense induction and epigenetic inheritance in plants. Trends Ecol. Evol. 27(11), 618–626 (2012).

149. Malmquist NA, Moss TA, Mecheri S, Scherf A, Fuchter MJ. Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms in Plasmodium falciparum. Proc. Natl Acad. Sci. USA 109(41), 16708–16713 (2012).

150. Sumanadasa SD, Goodman CD, Lucke AJ et al. Antimalarial activity of the anticancer histone deacetylase inhibitor SB939. Antimicrob. Agents Chemother. 56(7), 3849–3856 (2012).

151. Ay E, Banati F, Mezei M et al. Epigenetics of HIV infection: promising research areas and implications for therapy. AIDS Rev. 15(3), 181–188 (2013).


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