Katarzyna Szarc Vel Szic

" Matladi

Guy Haegeman

Wim Vanden Berghe
email: wim.vandenberghe@ua.ac.be

Nature or nurture: Let food be your epigenetic medicine in chronic inflammatory disorders

Numerous clinical, physiopathological and epidemiological studies have underlined the detrimental or beneficial role of nutritional factors in complex inflammation related disorders such as allergy, asthma, obesity, type 2 diabetes, cardiovascular disease, rheumatoid arthritis and cancer. Today, nutritional research has shifted from alleviating nutrient deficiencies to chronic disease prevention. It is known that lifestyle, environmental conditions and nutritional compounds influence gene expression. Gene expression states are set by transcriptional activators and repressors and are often locked in by cell-heritable chromatin states. Only recently, it has been observed that the environmental conditions and daily diet can affect transgenerational gene expression via "reversible" heritable epigenetic mechanisms.

Epigenetic changes in DNA methylation patterns at CpG sites (epimutations) or corrupt chromatin states of key inflammatory genes and noncoding RNAs, recently emerged as major governing factors in cancer, chronic inflammatory and metabolic disorders. Reciprocally, inflammation, metabolic stress and diet composition can also change activities of the epigenetic machinery and indirectly or directly change chromatin marks. This has recently launched re-exploration of anti-inflammatory bioactive food components for characterization of their effects on epigenome modifying enzymatic activities (acetylation, methylation, phosphorylation, ribosylation, oxidation, ubiquitination, sumoylation). This may allow to improve healthy aging by reversing disease prone epimutations involved in chronic inflammatory and metabolic disorders.

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A c c e p t e d M a n u s c r i p t

Introduction A large body of epidemiological and experimental data has demonstrated a direct link between chronic inflammation and complex diseases such as obesity, allergy, asthma, cardiovascular disease, type 2 diabetes, rheumatoid arthritis, bowel disease and several types of cancer. Nutrition, as the main aspect of the environment, is said to play a key role in some of this disparities, however, the molecular mechanisms involved still remain to be unraveled [START_REF] Boffetta | Fruit and vegetable intake and overall cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)[END_REF][START_REF] Bingham | Diet and cancer--the European Prospective Investigation into Cancer and Nutrition[END_REF][START_REF] Anand | Cancer is a preventable disease that requires major lifestyle changes[END_REF]. Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. However, most variants identified so far confer relatively small increments in risk, leaving many questions how the remaining "missing" heritability can be explained, although polygenic disease traits may account for some of this limitations [START_REF] Manolio | Finding the missing heritability of complex diseases[END_REF][START_REF] Maher | Personal genomes: The case of the missing heritability[END_REF].

Furthermore, genetics per se cannot explain the vast diversity of phenotypes. A substantial number of studies have shown that contstraint in the early life environment is associated with increased risk of cardiometabolic disease, affective disorders and cognitive decline, osteoporosis, allergy, inflammation and specific cancers. Furthermore, genetics per se cannot explain the vast diversity of phenotypes. The differences between identical twins and their different susceptibility to most diseases has recently been attributed to epigenetic changes which accumulate during life following exposure to different environmental conditions [START_REF] Fraga | Epigenetic differences arise during the lifetime of monozygotic twins[END_REF][START_REF] Fraga | Epigenetics and aging: the targets and the marks[END_REF][START_REF] Christensen | Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context[END_REF].

The contribution of epigenetic changes (epimutations) to human disease is probably underestimated. Epigenetics encompasses several extra-genetic processes such as DNA methylation (methylation of cytosines within CpG dinucleotides), histone tail modifications (including acetylation, phosphorylation, methylation, sumoylation, ribosylation and ubiquitination), noncoding RNA functions, regulation of polycomb group proteins and the epigenetic cofactor modifiers, all of which may alter gene expression but do not involve changes in the DNA sequence itself [START_REF] Lee | Stability of histone modifications across mammalian genomes: implications for 'epigenetic' marking[END_REF][START_REF] Vanden Berghe | Keeping up NF-kappaB appearances: epigenetic control of immunity or inflammation-triggered epigenetics[END_REF][START_REF] Chi | Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers[END_REF][START_REF] Guil | DNA methylomes, histone codes and miRNAs: tying it all together[END_REF][START_REF] Davalos | MicroRNAs and cancer epigenetics: a macrorevolution[END_REF]. The combinatorial nature of DNA methylation and histone modifications significantly extends the information potential of the genetic code.

In a large scale comparative study, authors concluded a lack of genetic factor in chronic obstructive pulmonary disorder (COPD), cardiovascular disease (CVD), rheumatoid arthritis and Crohn's disease, all typical examples of diseases with an important inflammatory component [START_REF] Plomin | The genetic basis of complex human behaviors[END_REF]. A recent survey of the global incidence of cancer shows that the age-adjusted cancer incidence in the Western world is above 300 cases per 100,000 population, whereas that in Asian countries is less than 100 cases per 100,000. Sedentary lifestyle, diet, obesity and metabolic syndrome have been named as the major contributors to this phenomena, which is further emphasized by the increase in cancer cases among immigrants from Asian to A c c e p t e d M a n u s c r i p t 4 Western countries [START_REF] Messina | Early intake appears to be the key to the proposed protective effects of soy intake against breast cancer[END_REF][START_REF] Shu | Soy food intake and breast cancer survival[END_REF]. As such, a reasonable good fraction of cancer deaths maybe prevented by modifying the diet composition (i.e. content of fiber, fruit, vegetable, fat/oil, protein, spices, cereals, xenobiotics) and regular physical exercise [START_REF] Anand | Cancer is a preventable disease that requires major lifestyle changes[END_REF][START_REF] Tennant | Targeting metabolic transformation for cancer therapy[END_REF]. Abnormalities in DNA methylation, histone modifications, chromatin remodelling and microRNA (miR) patterns [START_REF] Guil | DNA methylomes, histone codes and miRNAs: tying it all together[END_REF][START_REF] Lujambio | A microRNA DNA methylation signature for human cancer metastasis[END_REF][START_REF] Lujambio | CpG island hypermethylation of tumor suppressor microRNAs in human cancer[END_REF] are important hallmarks of inflammatory disease states and cancer [START_REF] Vanden Berghe | Keeping up NF-kappaB appearances: epigenetic control of immunity or inflammation-triggered epigenetics[END_REF][START_REF] Guil | DNA methylomes, histone codes and miRNAs: tying it all together[END_REF][START_REF] Davalos | MicroRNAs and cancer epigenetics: a macrorevolution[END_REF][START_REF] Esteller | Cancer epigenomics: DNA methylomes and histone-modification maps[END_REF][START_REF] Esteller | Epigenetics in cancer[END_REF][START_REF] Backdahl | Inflammatory signaling as mediator of epigenetic modulation in tissue-specific chronic inflammation[END_REF].

The most studied epigenetic lesion, which is DNA hypermethylation at the promoter region of many genes [START_REF] Esteller | Cancer epigenomics: DNA methylomes and histone-modification maps[END_REF][START_REF] Mulero-Navarro | Chromatin remodeling factor CHD5 is silenced by promoter CpG island hypermethylation in human cancer[END_REF], is proved to be responsible for silencing of more than 600 cancerrelated genes and this number is still rising. They include tumour suppressor genes, as well as genes involved in the cell-cycle regulation, DNA repair, angiogenesis, metastasis and apoptosis [START_REF] Herceg | Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors[END_REF]. On the other hand, global hypomethylation of the DNA is said to activate endoparasitic sequences and causes the global chromosome instability leading to various mutations and cancer progression [START_REF] Esteller | Epigenetics in cancer[END_REF]. Now, it is becoming clear that epigenetic changes complement genetic mutations and importantly drive the development and progression of various diseases ranging from allergy, asthma, rheumatoid arthritis, type 2 diabetes, obesity, bowel disease, cardiovascular disease and cancer [START_REF] Guil | DNA methylomes, histone codes and miRNAs: tying it all together[END_REF][START_REF] Davalos | MicroRNAs and cancer epigenetics: a macrorevolution[END_REF][START_REF] Esteller | Cancer epigenomics: DNA methylomes and histone-modification maps[END_REF][START_REF] Esteller | Epigenetics in cancer[END_REF][START_REF] Miller | Environmental epigenetics and asthma: current concepts and call for studies[END_REF][START_REF] Villeneuve | The Role of Epigenetics in the Pathology of Diabetic Complications[END_REF][START_REF] Schwartz | Epigenetics and environmental lung disease[END_REF][START_REF] Gluckman | Effect of in utero and early-life conditions on adult health and disease[END_REF][START_REF] Godfrey | Developmental origins of metabolic disease: life course and intergenerational perspectives[END_REF]. Recent successes of therapeutic intervention in chronic inflammatory diseases using epigenetic modifiers such as histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors has fuelled interest in exploring epigenomic maps of inflammatory disease states [START_REF]Moving AHEAD with an international human epigenome project[END_REF][START_REF] Altucci | Time for epigenetics[END_REF]. Interestingly, emerging data demonstrate the direct influence of certain anti-inflammatory dietary factors (for example polyphenols, isothiocyanates, epicatechins) and micronutrients (for example folic acid, selenium) on heritable gene expression and DNA methylation or chromatin remodelling [START_REF] Burdge | Nutrition, Epigenetics, and Developmental Plasticity: Implications for Understanding Human Diseas[END_REF][START_REF] Delage | Dietary manipulation of histone structure and function[END_REF][START_REF] Link | Cancer chemoprevention by dietary polyphenols: Promising role for epigenetics[END_REF][START_REF] Folmer | Naturally occurring regulators of histone acetylation/deacetylation[END_REF][START_REF] Hauser | Targeting epigenetic mechanisms: potential of natural products in cancer chemoprevention[END_REF][START_REF] Kontogiorgis | Natural Products from Mediterranean Diet: From Anti-Inflammatory Agents to Dietary Epigenetic Modulators[END_REF][START_REF] Kirk | Botanicals as epigenetic modulators for mechanisms contributing to development of metabolic syndrome[END_REF][START_REF] Fang | Dietary polyphenols may affect DNA methylation[END_REF][START_REF] Suzuki | Epigenetic control using natural products and synthetic molecules[END_REF]. Because epigenetic changes are reversible, developing drugs that control epigenetic regulation now attract substantial research investment, including the development of functional foods or supplements as nutrition based epigenetic modulators which will be discussed in more detail below [START_REF] Bingham | Diet and cancer--the European Prospective Investigation into Cancer and Nutrition[END_REF][START_REF]Moving AHEAD with an international human epigenome project[END_REF][START_REF] Arasaradnam | A review of dietary factors and its influence on DNA methylation in colorectal carcinogenesis[END_REF]

Extragenomic epigenetic information

The definition of "epigenetics" evolved during the past 50 years into the current and common definition of "heritable changes in gene function that cannot be explained by changes in DNA sequence, although some definitions have excluded heritability [START_REF] Berger | An operational definition of epigenetics[END_REF]. While "inheritance" and "heritability" strictly spoken, refer to intergenerational organismal phenomena, they are also widely used today for describing both molecular and phenotypic characteristics at the cellular level that are transmitted between mitotic cell division. Expression of our DNA genotype can A c c e p t e d M a n u s c r i p t 5 be twiddled by various volume knobs. Considerable cross-talk occurs between three main players in silencing: DNA methylation, histone modifications and noncoding RNAs. The chromatin template therefore serves as the major platform for epigenetic regulation in the form of DNA methylation, histone modifications and histone variants. More recently, an epigenetic role for RNA has also been demonstrated in normal situations as well as in disease [START_REF] Guil | DNA methylomes, histone codes and miRNAs: tying it all together[END_REF]. Before most activators of a gene access their DNA-binding sites, a transition from a condensed ("solenoid-like fiber") to a decondensed ("beads on a string") chromatin structure appears to take place. Conversely, the acquisition of a more condensed chromatin structure is often associated with gene silencing [START_REF] Chi | Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers[END_REF]. This structural restriction of chromatin on gene expression can be overcome by chromatin remodeling cofactor complexes, which reversibly modify (acetylation, phosphorylation, ubiquitylation, glycosylation, sumoylation) on lysine, arginistine, serine or threonine residues of amino-terminal histone tails. In general, DNA is wrapped around nucleosomes, which are arranged as regularly spaced beads (146 bp DNA/nucleosome) along the DNA. Typically, nucleosomes consist of a histone octamer of histones (H)2A/B, H3 and H4. The DNA bridging two adjacent nucleosomes is normally bound by the linker histone H1 and is termed linker DNA. While the core histones are bound relatively tightly to DNA, chromatin is largely maintained by the dynamic association with its architectural proteins. Since the discovery of histone modifying enzymes, N-terminal histone tails protruding from nucleosomes were found to be 'velcro patches' for (de)acetylases (HDAC/HAT), (de)methylases (HMT/HDMT), ubiquitin ligases, small ubiquitin-related modifier (SUMO) ligases, kinases, phosphatases, ribosylases, which together establish specific histone modification patterns involved in transcription [START_REF] Chi | Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers[END_REF]. Specific sets of histone modifications and/or variants are associated with genes that are actively transcribed or are repressed, a phenomenon defined as the "histone code" [START_REF] Chi | Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers[END_REF]. Since the modifications do not involve underlying changes in nucleotide or amino acid sequences, they are "above the genome" and as such termed "epigenomic". However, to establish specificity of epigenetic marks, histone modifying complexes have to be recruited to relevant genomic locations by DNA-binding proteins, RNAs or protein-RNA complexes that bind to their specific DNA sites as a consequence of their own binding specificities and cellular concentrations [START_REF] Perissi | Deconstructing repression: evolving models of co-repressor action[END_REF][START_REF] Vire | The Polycomb group protein EZH2 directly controls DNA methylation[END_REF][START_REF] Brenner | Myc represses transcription through recruitment of DNA methyltransferase corepressor[END_REF][START_REF] Hervouet | Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation[END_REF]. It cannot come from the enzymatic activities per se as neither DNMTs, nor enzymes which modify histones know which part of the genome needs to be tagged. Furthermore, there is now a large body of evidence showing that modifications of the histone tails provide signals ("binary switches") that are recognized by specific binding proteins, such as chromo-, bromoor tudor-domains which in turn can influence gene expresion and other chromatin functions A c c e p t e d M a n u s c r i p t 6 [START_REF] Seet | Reading protein modifications with interaction domains[END_REF][START_REF] Fischle | Talk is cheap--cross-talk in establishment, maintenance, and readout of chromatin modifications[END_REF][START_REF] Schreiber | Signaling network model of chromatin[END_REF]. The spatial and time-dependent combinations of histone modifications further increase the complexity of information contained in chromatin [START_REF] Chi | Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers[END_REF][START_REF] Fischle | Talk is cheap--cross-talk in establishment, maintenance, and readout of chromatin modifications[END_REF][START_REF] Schreiber | Signaling network model of chromatin[END_REF].

DNA methylation is the best-known epigenetic mark [START_REF] Esteller | Cancer epigenomics: DNA methylomes and histone-modification maps[END_REF][START_REF] Bird | DNA methylation patterns and epigenetic memory[END_REF]. It is catalyzed by two types of DNMTs: DNMT1 is a maintenance methyltransferase, whereas both DNMT3A and DNMT3B are de novo methyltransferases [START_REF] Jones | Rethinking how DNA methylation patterns are maintained[END_REF][START_REF] Law | Establishing, maintaining and modifying DNA methylation patterns in plants and animals[END_REF]. The role of DNMT2 in DNA methylation is minor, its enzymology being largely directed to tRNA. DNA methylation is normally associated with gene inactivation and it usually occurs in CpG dinucleotides. Alternatively, DNA methylation of transcription factor binding sites which prevents binding of repressor proteins, may paradoxically induce gene activation. CpGs are normally methylated when scattered throughout the genome, but are mostly unmethylated when they are clustered as CpG islands at 5" ends of many genes. Hypermethylation of CpG-rich promoters triggers local histone code modifications resulting in a cellular camouflage mechanism that sequesters gene promoters away from transcription factors and results in stable silencing of gene expression. DNA methylation at CpG dinucleotides occurs upon transfer of Sadenosylmethionine (SAM) on cytosine by DNMTs. Whereas DNMT3A/B are responsible for DNA methylation during development (differentiation), DNMT1 is in charge of maintaining DNA methylation patterns in DNA replication during cell division. In mammalian cells, the fidelity of maintenance of methylation is 97-99.9% per mitosis, whereas de novo methylation is as high as 3-5% per mitosis, thus creating possibilities for epigenetic changes.

DNA methylation also regulates genomic imprinting [START_REF] Lees-Murdock | DNA methylation reprogramming in the germ line[END_REF], Xchromosome inactivation [START_REF] Robertson | DNA methylation and human disease[END_REF] and silencing of repetitive sequences [START_REF] Miranda | DNA methylation: the nuts and bolts of repression[END_REF]. Although in most cases DNA methylation is a stable epigenetic mark, reduced levels of methylation can also be observed during development. This net loss of methylation can either occur passively by replication in the absence of cuntional maintenance methylation pathways, or actively, by removing methylated cytosines. In plants active demethylation is achieved in plants by DNA glycosylase activity, probably in combination with the base excision repair pathway. In mammals, coupling of 5-methylcytosine deaminase and thymine DNA glycosylase activities maybe responsible for DNA demethylation. Alternatively, a role for the 5hydroxymethylcytosine modification in mammalian DNA demethylation has also been proposed as an intermediate in an active DNA demethylation pathway involving DNA repair and 5-hydroxymethylcytosine-specific DNA glycosylase activity [START_REF] Law | Establishing, maintaining and modifying DNA methylation patterns in plants and animals[END_REF].

Although DNA methylation is the best-known epigenetic mark [START_REF] Jones | Rethinking how DNA methylation patterns are maintained[END_REF][START_REF] Scarano | DNA methylation 40 years later: Its role in human health and disease[END_REF][START_REF] Lande-Diner | Silence of the genes--mechanisms of long-term repression[END_REF], DNA methylation does not act alone. It occurs in the context of nucleosome positioning and histone modifications [START_REF] Lee | Stability of histone modifications across mammalian genomes: implications for 'epigenetic' marking[END_REF][START_REF] Vaissiere | Epigenetic interplay between histone modifications and DNA methylation in gene silencing[END_REF][START_REF] Chodavarapu | Relationship between nucleosome positioning and DNA methylation[END_REF]. For example, high resolution DNA methylation analysis has A c c e p t e d M a n u s c r i p t 7 revealed 10-base periodicities (i.e one helical turn) in the DNA methylation status of nucleosome-bound DNA and found that nucleosomal DNA was more highly methylated than flanking DNA [START_REF] Chodavarapu | Relationship between nucleosome positioning and DNA methylation[END_REF]. These data revealed that nucleosome positioning influences DNA methylation patterning of promoters and intron-exon boundaries throughout the genome and that DNA methyltransferases preferentially target nucleosome-bound DNA. Whether nucleosome strings provide a combinatory histone code is a matter of debate [START_REF] Lee | Stability of histone modifications across mammalian genomes: implications for 'epigenetic' marking[END_REF][START_REF] Chi | Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers[END_REF][START_REF] Guil | DNA methylomes, histone codes and miRNAs: tying it all together[END_REF][START_REF] Fischle | Talk is cheap--cross-talk in establishment, maintenance, and readout of chromatin modifications[END_REF][START_REF] Cosgrove | How does the histone code work?[END_REF][START_REF] Jenuwein | Translating the histone code[END_REF][START_REF] Margueron | The key to development: interpreting the histone code?[END_REF], but in any event, histone modifications influence gene activity and regulation. For example, acetylation of lysines is generally associated with transcriptional activation whereas lysine methylation can dictate either activation (e.g. H3K4, H3K36, H3K79) or suppression (e.g. H3K9, H3K27 or H4K20). Specific histone modifications have been shown to be associated with DNA hypermethylation of CpG islands, including deacetylation of histones H3 and H4, loss of H3K4me, and gain of H3K9me3 and H3K27me3 [START_REF] Robertson | Genome-wide relationship between histone H3 lysine 4 mono-and tri-methylation and transcription factor binding[END_REF][START_REF] Jones | Epigenetics: reversing the 'irreversible[END_REF]. More importantly, specific histone modifications have been implicated in several diseases, such as cancer and CVD, while recently, evidence for modifications in allergic asthma and COPD is also emerging [START_REF] Esteller | Epigenetics in cancer[END_REF][START_REF] Miller | Environmental epigenetics and asthma: current concepts and call for studies[END_REF][START_REF] Pons | Epigenetic histone acetylation modifiers in vascular remodelling: new targets for therapy in cardiovascular disease[END_REF][START_REF] Bertram | Transgenerational effects of prenatal nutrient restriction on cardiovascular and hypothalamic-pituitary-adrenal function[END_REF][START_REF] Kim | DNA methylation as a biomarker for cardiovascular disease risk[END_REF][START_REF] Wierda | Epigenetics in atherosclerosis and inflammation[END_REF]. DNA methylation marks are recognized by DNA methylbinding proteins (MBD) which can interact with corepressor-associated enzymes (i.e.

HDACs, enhancer of zeste homologue (EZH)2, ...), thus further linking DNA methylation and chromatin regulation [START_REF] Perissi | Deconstructing repression: evolving models of co-repressor action[END_REF][START_REF] Perissi | Controlling nuclear receptors: the circular logic of cofactor cycles[END_REF]. Altogether, "histone code" may only become biologically meaningful at the level of the chromatin fiber ("chromatin regulatory code") which, upon integration of conformations of multiple nucleosomes, translates allosteric changes into specific gene (cluster) activities, in order to establish specific regulatory programs at the genome level [START_REF] Chi | Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers[END_REF][START_REF] Nunez | Nuclear organization in the 3D space of the nucleus -cause or consequence?[END_REF][START_REF] Nolis | Transcription factors mediate long-range enhancer-promoter interactions[END_REF][START_REF] Fujioka | A chromatin insulator mediates transgene homing and very long-range enhancer-promoter communication[END_REF]. In analogy to allosteric control of enzymes, specific gene activity may be determined by the spatial organization (compartmentalization in discrete territories) and structural landscape (three-dimensional structure) of a gene locus, by altering the higher order structure of chromatin (cis mechanism) or by generating a binding platform for effector proteins (trans mechanisms) [START_REF] Nunez | Nuclear organization in the 3D space of the nucleus -cause or consequence?[END_REF][START_REF] Nolis | Transcription factors mediate long-range enhancer-promoter interactions[END_REF][START_REF] Metivier | Transcription in four dimensions: nuclear receptordirected initiation of gene expression[END_REF][START_REF] Lieberman-Aiden | Comprehensive mapping of long-range interactions reveals folding principles of the human genome[END_REF].

There is good evidence that also noncoding RNAs regulate chromatin architecture [START_REF] Guil | DNA methylomes, histone codes and miRNAs: tying it all together[END_REF][START_REF] Taft | Noncoding RNAs: regulators of disease[END_REF][START_REF] Taft | Tiny RNAs associated with transcription start sites in animals[END_REF][START_REF] Mattick | A global view of genomic information -moving beyond the gene and the master regulator[END_REF][START_REF] Mattick | RNA regulation of epigenetic processes[END_REF][START_REF] Tsai | Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes[END_REF][START_REF] Gupta | Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis[END_REF]. The term noncoding RNA (ncRNA) is commonly employed for RNA that does not encode a protein. Although it has been generally assumed that most genetic information is transacted by proteins, recent evidence suggests that the majority of the genomes of mammals and other complex organisms is in fact transcribed into ncRNAs, many of which are alternatively spliced and/or processed into smaller products. Besides tRNA and rRNA, these ncRNAs include long-noncodingRNAs (lncRNAs), microRNAs (miRNAs) and tinyRNAs (tiRNAs) as well as several other classes of, sometimes yet-to-be-discovered, small regulatory transcription (enhancer function), RNA splicing, editing, translation and turnover [START_REF] Santa | A large fraction of extragenic RNA pol II transcription sites overlap enhancers[END_REF]. RNA regulatory networks may determine most of our complex characteristics and play a significant role in disease [START_REF] Santa | A large fraction of extragenic RNA pol II transcription sites overlap enhancers[END_REF]. For example, miRNAs can change expression levels of the epigenetic machinery (DNMT, HDAC, sirtuin (SIRT), polycomb (Pc) proteins, etc.) by posttranscriptional gene regulation involving base pairing with 3"untranslated (UTR) regions in their target mRNAs resulting in mRNA degradation or inhibition of translation [START_REF] Guil | DNA methylomes, histone codes and miRNAs: tying it all together[END_REF][START_REF] Lujambio | A microRNA DNA methylation signature for human cancer metastasis[END_REF][START_REF] Lujambio | CpG island hypermethylation of tumor suppressor microRNAs in human cancer[END_REF][START_REF] Lujambio | How epigenetics can explain human metastasis: a new role for microRNAs[END_REF]. Alternatively, long ncRNAs and tiRNAs can regulate gene expression and/or DNA methylation by promoter association [START_REF] Taft | Noncoding RNAs: regulators of disease[END_REF][START_REF] Taft | Tiny RNAs associated with transcription start sites in animals[END_REF][START_REF] Santa | A large fraction of extragenic RNA pol II transcription sites overlap enhancers[END_REF]. DNA-methylation can thus also be RNAdirected [START_REF] Guil | DNA methylomes, histone codes and miRNAs: tying it all together[END_REF][START_REF] Mahfouz | RNA-directed DNA methylation: Mechanisms and functions[END_REF].

Inflammatory and metabolic stress fuel epigenetic plasticity

Inflammation is a fundamental adaptation to the loss of cellular and tissue homeostasis covering many important processes, including host defense, tissue remodeling and repair, and the regulation of metabolism. The complexity of the inflammatory response requires that its many functional programs are controlled coordinately in some situations but independently in others [START_REF] Medzhitov | Transcriptional control of the inflammatory response[END_REF][START_REF] Pasparakis | Regulation of tissue homeostasis by NF-kappaB signaling: implications for inflammatory diseases[END_REF]. This is achieved through multiple mechanisms that operate at different levels, including alterations in the composition of immune cells in tissues, changes in cell responsiveness to inflammatory stimuli, regulation of signaling pathways and epigenetic control of gene expression.

Cell-specific mechanisms operate at the level of different cell types, and include regulation of their recruitment and activation. The cellular component involves the movement of leukocytes from blood vessels into the inflamed tissue, while leukocytes are involved in the initiation and maintenance of inflammation [START_REF] Medzhitov | Transcriptional control of the inflammatory response[END_REF][START_REF] Medzhitov | Origin and physiological roles of inflammation[END_REF]. Macrophages participate in host defense, immunity and inflammatory responses, where they are potently activated resulting in the production of pro-inflammatory cytokines, oxygen and nitrogen species and eicosanoids.

Acute inflammation is mediated by granulocytes or polymorphonuclear leucocytes, while chronic inflammation is mediated by mononuclear cells such as monocytes and macrophages which can be further stimulated to maintain inflammation through the action of an adaptive cascade involving dendritic cells, T-and B-lymphocytes and antibodies [START_REF] Medzhitov | Transcriptional control of the inflammatory response[END_REF][START_REF] Cobb | T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer[END_REF][START_REF] Palstra | The beta-globin nuclear compartment in development and erythroid differentiation[END_REF][START_REF] Wilson | Epigenetic control of T-helper-cell differentiation[END_REF][START_REF] Lambrecht | Taking our breath away: dendritic cells in the pathogenesis of asthma[END_REF][START_REF] Hammad | Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma[END_REF][START_REF] Messi | Memory and flexibility of cytokine gene expression as separable properties of human T(H)1 and T(H)2 lymphocytes[END_REF].

Imbalances in control of haematopoesis and lineage differentiation of Th1, Th2 and Treg cells have a major impact on prevalence of sensitization to allergens and allergic diseases and has A c c e p t e d M a n u s c r i p t 9 reached epidemic proportions in Western societies [START_REF] Shaheen | The developmental origins of asthma: does epigenetics hold the key?[END_REF][START_REF] Adcock | Epigenetics and airways disease[END_REF][START_REF] Lambrecht | Biology of lung dendritic cells at the origin of asthma[END_REF][START_REF] Hammad | House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells[END_REF]. Furthermore, tumors are typically infiltrated with immune cells and inflammation which impacts on most, if not all, stages of tumorigenesis [START_REF] Grivennikov | Inflammation and oncogenesis: a vicious connection[END_REF][START_REF] Balkwill | Smoldering and polarized inflammation in the initiation and promotion of malignant disease[END_REF][START_REF] Balkwill | Cancer and inflammation: implications for pharmacology and therapeutics[END_REF][START_REF] Aggarwal | Inflammation and cancer: how friendly is the relationship for cancer patients?[END_REF]. Moreover, most cancers contain an inflammatory infiltrate that is hijacked by tumor cells to promote angiogenesis, tissue invasion and cell proliferation. What is more, overnutrition and obesity activate the immune system which at long-term switches to chronic inflammatory condition that is as fertile soil for cancer development [START_REF] Anand | Cancer is a preventable disease that requires major lifestyle changes[END_REF][START_REF] Solinas | JNK1 and IKK{beta}: molecular links between obesity and metabolic dysfunction[END_REF][START_REF] Park | Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression[END_REF][START_REF] Olefsky | IKKepsilon: a bridge between obesity and inflammation[END_REF][START_REF] Zhang | Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity[END_REF][START_REF] Hotamisligil | Endoplasmic reticulum stress and the inflammatory basis of metabolic disease[END_REF][START_REF] Mandl | Endoplasmic reticulum: nutrient sensor in physiology and pathology[END_REF].

Signal-specific mechanisms operate at the level of pathways which for example activate the key transcription factor nuclear factor-κB (NFκB). Among all the mediators and cellular effectors of inflammation, NFκB is perhaps the central transcription factor, which regulates expression of more than 400 genes [START_REF] Ghosh | New regulators of NF-kappaB in inflammation[END_REF][START_REF] Karin | NF-kappaB: linking inflammation and immunity to cancer development and progression[END_REF][START_REF] Chen | Shaping the nuclear action of NF-kappaB[END_REF]. At the same time, it is responsible for many aspects of inflammatory disease and malignancy by inducing transcription of soluble mediators that amplify inflammation, angiogenesis and neoplastic cell proliferation, and affect progression to more aggressive disease states [START_REF] Grivennikov | Inflammation and oncogenesis: a vicious connection[END_REF]. promoter, was found to silence its expression in metastatic prostate carcinoma [START_REF] Hervouet | Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation[END_REF][START_REF] Santourlidis | Hypermethylation of the tumor necrosis factor receptor superfamily 6 (APT1, Fas, CD95/Apo-1) gene promoter at rel/nuclear factor kappaB sites in prostatic carcinoma[END_REF].

Surprisingly, depletion of NFκB can also trigger DNA demethylation and gene reactivation of the Fructose-1,6-biphosphatase-1 (FBP1) illustrating gene-specific epigenetic effects which may further depend on posttranslational NFκB modifications [START_REF] Dong | Repression of gene expression by unphosphorylated NF-kappaB p65 through epigenetic mechanisms[END_REF][START_REF] Liu | Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis[END_REF].

Of special note, whereas studies with epigenetic drugs (azacytidin, suberoylanilide hydroxamic acid (SAHA)) frequently focus on reactivation of silenced tumor suppressor genes, these compounds also boost gene expression of inflammatory oncogenes such as IL6 which promote aggressive carcinogenesis, cancer stem cell proliferation, metastasis and hormone resistance [START_REF] Aggarwal | Inflammation and cancer: how friendly is the relationship for cancer patients?[END_REF][START_REF] Yu | STATs in cancer inflammation and immunity: a leading role for STAT3[END_REF][START_REF] Iliopoulos | An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation[END_REF][START_REF] Wang | Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth[END_REF][START_REF] Min | An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB[END_REF][START_REF] Maeda | Ikappa B kinasebeta/nuclear factor-kappaB activation controls the development of liver metastasis by way of interleukin-6 expression[END_REF][START_REF] Grivennikov | IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer[END_REF][START_REF] Naugler | The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer[END_REF][START_REF] Suttana | Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols[END_REF]. Furthermore, elevated IL6 gene expression is able to trigger epigenetic changes of tumor suppressor genes via regulation of DNMTs [START_REF] Peng | Epigenetic silencing of the human nucleotide excision repair gene, hHR23B, in interleukin-6responsive multiple myeloma KAS-6/1 cells[END_REF][START_REF] Pompeia | Microarray analysis of epigenetic silencing of gene expression in the KAS-6/1 multiple myeloma cell line[END_REF][START_REF] Hodge | Epigenetic Silencing of Manganese Superoxide Dismutase (SOD-2) in KAS 6/1 Human Multiple Myeloma Cells Increases Cell Proliferation[END_REF][START_REF] Hodge | IL-6 enhances the nuclear translocation of DNA cytosine-5-methyltransferase 1 (DNMT1) via phosphorylation of the nuclear localization sequence by the AKT kinase[END_REF],

microRNAs [START_REF] Iliopoulos | An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation[END_REF][START_REF] Braconi | MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes[END_REF][START_REF] Meng | Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes[END_REF] and histone methyltransferases (Ezh2) [START_REF] Croonquist | The polycomb group protein enhancer of zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype[END_REF]. This suggests that epigenetic regulators themselves and methylation of tumor suppressor genes are also susceptible to dynamic inflammatory control [START_REF] Iliopoulos | An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation[END_REF][START_REF] Peng | Epigenetic silencing of the human nucleotide excision repair gene, hHR23B, in interleukin-6responsive multiple myeloma KAS-6/1 cells[END_REF][START_REF] Braconi | MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes[END_REF][START_REF] Meng | Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes[END_REF][START_REF] Mathews | Epigenetic gene regulation in stem cells and correlation to cancer[END_REF][START_REF] Kawasaki | Targeting cancer stem cells with phytochemicals[END_REF][START_REF] Hodge | Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation[END_REF][START_REF] Hodge | Interleukin-6 regulation of the human DNA methyltransferase (HDNMT) gene in human erythroleukemia cells[END_REF], which adds an extra level of complexity to the cancer-inflammation link.

Furthermore, besides epigenetic changes in neoplastic cells, inflammatory stimuli in the tumor microenvironment can also epigenetically reprogram tumor-associated immune cells, as demonstrated for the NFB-dependent histone demethylase JMJD3 which determines cell fate and transdifferentiation of tumor-associated macrophages [START_REF] Santa | The histone H3 lysine-27 demethylase JMJD3 links inflammation to inhibition of polycombmediated gene silencing[END_REF][START_REF] Kim | DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging[END_REF]. Reports on epigenetic events in cancer are traditionally produced from analyses on "bulk" tumor samples, i.e.

without distinction between neoplastic cells on one hand and the tumoral stroma on the other.

The pro-inflammatory micro-environment that drives many tumor types is as such capable of triggering these epigenetic alterations within cancer progenitor cells, alterations which can substitute for genetic defects later in tumour progression [START_REF] Iliopoulos | An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation[END_REF][START_REF] Sharma | A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations[END_REF]. However, also tumor stromal components (which include bone-marrow-derived cells, tumor-associated macrophages) are a target of epigenetic events [START_REF] Messi | Memory and flexibility of cytokine gene expression as separable properties of human T(H)1 and T(H)2 lymphocytes[END_REF][START_REF] Santa | The histone H3 lysine-27 demethylase JMJD3 links inflammation to inhibition of polycombmediated gene silencing[END_REF][START_REF] Dijsselbloem | A critical role for p53 in the control of NF-kappaB-dependent gene expression in TLR4stimulated dendritic cells exposed to Genistein[END_REF]. Similarly, in atherosclerotic plaques, interplay between monocytes, macrophages and vascular endothelium will trigger various epigenetic alterations in the different cell types in the plaque microenvironment [START_REF] Wierda | Epigenetics in atherosclerosis and inflammation[END_REF][START_REF] Galkina | Vascular adhesion molecules in atherosclerosis[END_REF][START_REF] Galkina | Immune and inflammatory mechanisms of atherosclerosis (*)[END_REF][START_REF] Lund | Atherosclerosis, lipids, inflammation and epigenetics[END_REF][START_REF] Lund | Atherosclerosis risk factors can impose aberrant DNA methylation patterns: a tale of traffic and homocysteine[END_REF][START_REF] Lund | Epigenetics, transgenerational effects and risk factors for atherosclerosis[END_REF][START_REF] Turunen | Epigenetics and atherosclerosis[END_REF][START_REF] Yu | SIRT1: a novel target to prevent atherosclerosis[END_REF][START_REF] Zaina | Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia?[END_REF]. Besides inflammatory factors, the micro-environment also contains free radicals produced by neutrophils, macrophages, endothelial and other cells. Reactive Oxygen Species (ROS) such as will affect chromatin dynamics in tumor-associated immune cells [START_REF] Franco | Oxidative stress, DNA methylation and carcinogenesis[END_REF][START_REF] Forneris | LSD1: oxidative chemistry for multifaceted functions in chromatin regulation[END_REF][START_REF] Illi | NO sparks off chromatin: tales of a multifaceted epigenetic regulator[END_REF][START_REF] Brewer | Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories[END_REF][START_REF] Carta | DAMPs and inflammatory processes: the role of redox in the different outcomes[END_REF].

One of the key functional characteristics of macrophages is that they can be programmed to deal most effectively with a given kind of inciting stimulus. In the lung for example, resident alveolar macrophages are continuously encountering inhaled substances due to their exposed position in the alveolar lumen [START_REF] Shaheen | The developmental origins of asthma: does epigenetics hold the key?[END_REF]. To avoid collateral damage to mucosal epithelium in response to harmless antigens, they are kept in a quiescent state, producing little inflammatory cytokines and displaying poor phagocytic activity. In the vessel wall, macrophages can scavenge large amounts of lipid, and differentiate into lipid-laden foamy cells [START_REF] Galkina | Immune and inflammatory mechanisms of atherosclerosis (*)[END_REF]. As putative precursors for microglia and osteoclasts, monocytes may also be involved in the physiology of the central nervous system and in bone remodelling. Dendritic cells (DC) are also part of the monocytic phagocytic system and are the professional antigen presenting cells of the immune system that bridge innate and adaptive immunity [START_REF] Hammad | Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma[END_REF]. DC cells come in many flavours and it is clear now that there are multiple pathways to develop DC from monocytes.

The complexity of the monocytic phagocytic system requires that its many functional programmes are controlled coordinately in some situations, but separately in others. It is now clear that epigenetic mechanisms can lead to time-dependent and stimulus-specific alterations in the expresssion of functional modules [START_REF] Wen | Dendritic cells at the interface of innate and acquired immunity: the role for epigenetic changes[END_REF]. Epigenetic modifications like histone modifications and CpG-island methylation in promotor regions of critical transcription factors (so called masterswitch transcription factors) of all of these functional programmes have been described and are controlled by microRNAs, DNMTs, HDAC, histone acetylases (HAT CBP/p300, p/CAF) histone lysine methylases (EZH2, CARM, PRMT) and demethylases (LSD1, JMJD3) [START_REF] Ng | Dynamic protein methylation in chromatin biology[END_REF][START_REF] Klose | Regulation of histone methylation by demethylimination and demethylation[END_REF]. Emerging research indicates that epigenetic mechanisms that control the lineage development and polarization of monocytic phagocytic system and Th1, Th2 and Treg cells can be transmitted across multiple generations [START_REF] Medzhitov | Transcriptional control of the inflammatory response[END_REF][START_REF] Wilson | Epigenetic control of T-helper-cell differentiation[END_REF][START_REF] Jhunjhunwala | Chromatin architecture and the generation of antigen receptor diversity[END_REF][START_REF] Parra | Epigenetic events during B lymphocyte development[END_REF].

Smoking, diesel exhaust, diet conditions, hygiene, dust mite, obesity seem have major influence on epigenetic programming of immune cell populations and inflammatory disease severity in asthma, allergy, rheumatoid arthritis, bowel disease [START_REF] Martino | Silent mysteries: epigenetic paradigms could hold the key to conquering the epidemic of allergy and immune disease[END_REF][START_REF] Prescott | Asthma and pregnancy: emerging evidence of epigenetic interactions in utero[END_REF][START_REF] Karouzakis | Epigenetic control in rheumatoid arthritis synovial fibroblasts[END_REF][START_REF] Patel | Epigenetic mechanisms in lupus[END_REF][START_REF] Rodriguez-Canales | Identification of a unique epigenetic sub-microenvironment in prostate cancer[END_REF][START_REF] Hewagama | The genetics and epigenetics of autoimmune diseases[END_REF][START_REF] Barnett | Investigating micronutrients and epigenetic mechanisms in relation to inflammatory bowel disease[END_REF]. Similarly, hypertension, obesity and lack of physical activity can have longlasting effects on epigenetic reprogramming of monocytes/macrophages and endothelial cells promoting differentiation into more proatherogenic phenotypes and increased risk of cardiovascular disease [START_REF] Wierda | Epigenetics in atherosclerosis and inflammation[END_REF][START_REF] Lund | Atherosclerosis, lipids, inflammation and epigenetics[END_REF][START_REF] Lund | Epigenetics, transgenerational effects and risk factors for atherosclerosis[END_REF][START_REF] Turunen | Epigenetics and atherosclerosis[END_REF][START_REF] Yu | SIRT1: a novel target to prevent atherosclerosis[END_REF][START_REF] Zaina | Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia?[END_REF][START_REF] Zhang | Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice[END_REF].

A c c e p t e d M a n u s c r i p t

Nutri-epigenomics: lifelong remodelling of our epigenomes by nutritional, phytochemical and metabolic factors

Human epidemiological studies and appropriately designed dietary interventions in animal models have provided considerable evidence to suggest that maternal nutritional imbalance and metabolic disturbances, during critical time windows of development, may have a persistent effect on the health of offspring and may even be transmitted to the next generation [START_REF] Godfrey | Developmental origins of metabolic disease: life course and intergenerational perspectives[END_REF][START_REF] Burdge | Nutrition, Epigenetics, and Developmental Plasticity: Implications for Understanding Human Diseas[END_REF][START_REF] Cooney | Germ cells carry the epigenetic benefits of grandmother's diet[END_REF][START_REF] Weaver | Shaping adult phenotypes through early life environments. Birth Defects Research Part C[END_REF][START_REF] Aguilera | Epigenetics and environment: a complex relationship[END_REF][START_REF] Youngson | Transgenerational epigenetic effects[END_REF][START_REF] Gallou-Kabani | Nutri-epigenomics: lifelong remodelling of our epigenomes by nutritional and metabolic factors and beyond[END_REF]. This has led to the hypothesis of ""fetal programming"" and new term ""developmental origin of health and disease"" (DOHaD): common disorders, such as obesity, cardiovascular disease (CVD), diabetes, hypertension, asthma, cancer and even schizophrenia, take root in early nutrition during gestation and continues during lactation [START_REF] Gluckman | Effect of in utero and early-life conditions on adult health and disease[END_REF][START_REF] Burdge | Nutrition, Epigenetics, and Developmental Plasticity: Implications for Understanding Human Diseas[END_REF][START_REF] Anway | Epigenetic transgenerational actions of endocrine disruptors and male fertility[END_REF][START_REF] Anway | Epigenetic transgenerational actions of endocrine disruptors[END_REF][START_REF] Jirtle | Environmental epigenomics and disease susceptibility[END_REF][START_REF] Barker | The maternal and fetal origins of cardiovascular disease[END_REF][START_REF] Jackson | Diet, nutrition and modulation of genomic expression in fetal origins of adult disease[END_REF][START_REF] Chmurzynska | Fetal programming: link between early nutrition, DNA methylation, and complex diseases[END_REF].

The various non-Mendelian features of metabolic disease, cancer or chronic inflammatory disorders, clinical differences between men and women or monozygotic twins and fluctuations in the course of the disease are consistent with epigenetic mechanisms in the influence of fetal and/or lifelong nutrition or stochastic events on adult phenotype [29, 32, 204-208, 215, 216]. Thus, lifetime shapes the multitude of epigenomes not only within, but also across generations [START_REF] Godfrey | Developmental origins of metabolic disease: life course and intergenerational perspectives[END_REF][START_REF] Youngson | Transgenerational epigenetic effects[END_REF]. Interest in transgenerational epigenetic effects of food components has been fueled by observations in Agouti mice fed with a soy polyphenol diet, which revealed epigenetic changes in DNA methylation patterns in their offspring and protected against diabetes, obesity and cancer across multiple generations [START_REF] Dolinoy | Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome[END_REF][START_REF] Dolinoy | Environmental epigenomics in human health and disease[END_REF][219].

However, only weak transgenerational effects could be observed with soy polyphenols in Daphnia Magna, despite the presence of functional DNMTs [START_REF] Vandegehuchte | Direct and transgenerational impact on Daphnia magna of chemicals with a known effect on DNA methylation[END_REF]. Feeding pregnant mice with a diet rich in methyl donors altered DNA methylation at well defined CpG regions which led to decreased transcription of Runx3 and more sever asthma in offspring. Bronchial biopsies and alveolar macrophages of asthmatics revealed a disturbed epigenetic regulation of gene expression (increased HAT and decreased HDAC2 activity) [START_REF] Miller | Prenatal maternal diet affects asthma risk in offspring[END_REF]. Furthermore, the honeybee (Apis mellifera) is probably the clearest example of induction of alternative phenotypes and epigenotypes by nutrition in early life [START_REF] Gabor Miklos | Epigenomic communication systems in humans and honey bees: From molecules to behavior[END_REF]. Female bees are genetic clones.

However, queens are distinct from workers in their morphology, capacity to reproduce, behavior, and longevity. The difference between the queen and worker castes lies in the exposure of the genetically identical larvae to royal jelly, an as yet incompletely defined mixture of proteins, amino acids, vitamins, lipids, and other nutrients [START_REF] Kucharski | Nutritional control of reproductive status in honeybees via DNA methylation[END_REF][START_REF] Maleszka | Epigenetic integration of environmental and genomic signals in honey bees: the critical interplay of nutritional, brain and reproductive networks[END_REF][START_REF] Foret | Epigenetic regulation of the honey bee transcriptome: unravelling the nature of methylated genes[END_REF].

Studies of human populations following famine have suggested that pathologies in later life are dependent on the timing of nutritional insult during pregnancy. Follow up of the Dutch Hunger Winter cohort showed that cardiovascular disease was more prevalent in offspring of the time of nutrional insult [START_REF] Painter | Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life[END_REF][START_REF] Lumey | Transgenerational effects of prenatal exposure to the Dutch famine[END_REF][START_REF] Roseboom | The Dutch famine and its long-term consequences for adult health[END_REF]. Also paternal patterns of nutrition during the prepubertal growth period in children in Överkalix, in Sweden during the nineteenth century are associated with differential risk of early cardiovascular death in their grandchildren [START_REF] Whitelaw | Epigenetics: sins of the fathers, and their fathers[END_REF][START_REF] Kaati | Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period[END_REF]. Today, various different epigenetic changes have already been characterized which are involved in atherogenesis [START_REF] Gluckman | Effect of in utero and early-life conditions on adult health and disease[END_REF][START_REF] Godfrey | Developmental origins of metabolic disease: life course and intergenerational perspectives[END_REF][START_REF] Pons | Epigenetic histone acetylation modifiers in vascular remodelling: new targets for therapy in cardiovascular disease[END_REF][START_REF] Kim | DNA methylation as a biomarker for cardiovascular disease risk[END_REF][START_REF] Hanson | Developmental processes and the induction of cardiovascular function: conceptual aspects[END_REF]. Hypercholesterolemia, obesity, hyperhomocysteinemia, high glucose are important CVD risk factors which are implicated in enhanced inflammatory signaling and long-lasting effects are driven by epigenetic reprogramming, promoting differentiation of monocytes/macrophages into more proatherogenic phenotypes [START_REF] Wierda | Epigenetics in atherosclerosis and inflammation[END_REF][START_REF] Lund | Atherosclerosis risk factors can impose aberrant DNA methylation patterns: a tale of traffic and homocysteine[END_REF][START_REF] Lund | Epigenetics, transgenerational effects and risk factors for atherosclerosis[END_REF][START_REF] Waldo | Heterogeneity of human macrophages in culture and in atherosclerotic plaques[END_REF]. Recent evidence suggests that the pathogenetic role of hyperhomocysteinemia in vascular diseases might be mediated via Adenosyl-homocystein (Hcy) accumulation and DNA methylation. Hcy competes with Sadenosylmethionine (SAM; the methyl-group donor) for binding on DNMT, which may lead to passive loss of methylation in replicating DNA. High blood Hcy levels correlate with DNA hypomethylation and atherosclerosis and can lead to a 35% reduction in DNA methylation status of peripheral blood lymphocytes [START_REF] Sharma | Mining literature for a comprehensive pathway analysis: a case study for retrieval of homocysteine related genes for genetic and epigenetic studies[END_REF][START_REF] Chen | Regulation of homocysteine metabolism and methylation in human and mouse tissues[END_REF][START_REF] Jiang | Hyperhomocysteinemia-mediated DNA hypomethylation and its potential epigenetic role in rats[END_REF][START_REF] Kim | Effect of folate deficiency on placental DNA methylation in hyperhomocysteinemic rats[END_REF]. Similarly, insulin, glucose folate or flavanol-rich diets interfere with the methyldonor metabolism and the available pool of Sadenosylmethionine, resulting in DNA methylation changes [START_REF] Kim | Effect of folate deficiency on placental DNA methylation in hyperhomocysteinemic rats[END_REF][START_REF] Bistulfi | Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer cells[END_REF][START_REF] Ghoshal | A folate-and methyldeficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of F344 rats[END_REF][START_REF] Ulrich | Modeling folate, one-carbon metabolism, and DNA methylation[END_REF]. In contrast, very few studies have focused on impact of dietary methyldonors on histone methylation, which is also affected by alterations in SAM/SAH ratios [START_REF] Sharma | Mining literature for a comprehensive pathway analysis: a case study for retrieval of homocysteine related genes for genetic and epigenetic studies[END_REF][START_REF] Pogribny | Methyl deficiency, alterations in global histone modifications, and carcinogenesis[END_REF]. As such, specific dietary classes of functional food maybe designed as therapeutic epigenetic modulators in lifestyle disease, such as metabolic disorders (diabetes), cardiovascular disease, asthma/COPD, rheumatoid arthritis.

Epidemiologic and medical anthropological studies have indicated that flavanol-rich diets are inversely associated with cardiovascular risk [START_REF] Manach | Polyphenols and prevention of cardiovascular diseases[END_REF][START_REF] Fisher | Aging and vascular responses to flavanol-rich cocoa[END_REF][START_REF] Sies | Cocoa polyphenols and inflammatory mediators[END_REF][START_REF] Heiss | Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers[END_REF][START_REF] Baur | Therapeutic potential of resveratrol: the in vivo evidence[END_REF][START_REF] Bertelli | Grapes, wines, resveratrol, and heart health[END_REF]. Locus-specific DNA methylation changes, both hyper-and hypomethylation, also occur at the promoter level of several genes involved in the pathogenesis of atherosclerosis, such as extracellular superoxide dismutase (SOD), hormone receptors (glucocorticoid receptor (GR), estrogen receptor (ER), peroxisome proliferator-activated receptor (PPAR), arylhydrocarbon receptor, AhR, liver X receptor (LXR)), endothelial and inducible nitric oxide synthase (iNOS/eNOS), 15-lipoxygenase (LOX), fibroblast growth factor (FGF)2, hypoxia-inducible factor (HIF)1, myc, insulator CCCTC binding factor (CTCF) and metalloproteases (MMPs) [START_REF] Wierda | Epigenetics in atherosclerosis and inflammation[END_REF][START_REF] Turunen | Epigenetics and atherosclerosis[END_REF][START_REF] Van Straten | The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction[END_REF][START_REF] Burdge | Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations[END_REF][START_REF] Lillycrop | Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring[END_REF]. In a proatherogenic murine model, DNA-methylation polymorphisms preceded the appearance of histological signs of atherosclerosis [START_REF] Lund | Atherosclerosis risk factors can impose aberrant DNA methylation patterns: a tale of traffic and homocysteine[END_REF][START_REF] Lund | Epigenetics, transgenerational effects and risk factors for atherosclerosis[END_REF]. Interestingly, involvement of the inducible differentiation is susceptible to inflammatory pathways and oxidative stress [START_REF] Santa | The histone H3 lysine-27 demethylase JMJD3 links inflammation to inhibition of polycombmediated gene silencing[END_REF]. A role for the JMJD1A demethylase was demonstrated in metabolic gene expression and obesity resistance [START_REF] Tateishi | Role of Jhdm2a in regulating metabolic gene expression and obesity resistance[END_REF]. Furthermore, it was found that knockdown of the LSD1 demethylase affected monocyte adherence in a proatherogenic diabetic mouse model [START_REF] Reddy | Role of the lysinespecific demethylase 1 in the proinflammatory phenotype of vascular smooth muscle cells of diabetic mice[END_REF]. This suggests that LSD1 contribute to metabolic memory through long-term changes in gene expression via alterations in chromatin structure [START_REF] El-Osta | Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia[END_REF][START_REF] Brasacchio | Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail[END_REF].

Poor maternal nutrition has also been associated with increased risk of type 2 diabetes mellitus over several generations in North American Indians [START_REF] Attig | Nutritional developmental epigenomics: immediate and long-lasting effects[END_REF][START_REF] Gallou-Kabani | Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic[END_REF]. Individuals with metabolic syndrome, obesity and type II diabetes (T2D) CVD may show a lifelong imbalance between energy intake and energy expenditure due to incorrect epigenetic programming during their early development as a result of placental insufficiency, inadequate maternal nutrition, metabolic disturbances or neonatal medication [START_REF] Weaver | Shaping adult phenotypes through early life environments. Birth Defects Research Part C[END_REF][START_REF] Attig | Nutritional developmental epigenomics: immediate and long-lasting effects[END_REF][START_REF] Gallou-Kabani | Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic[END_REF][START_REF] Karemaker | Effects of neonatal dexamethasone treatment on the cardiovascular stress response of children at school age[END_REF][START_REF] Barres | Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density[END_REF][START_REF] Plagemann | Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding[END_REF][START_REF] Plagemann | Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome[END_REF].

Recently, evidence emerged that also timing (preconception, pregnancy, lactation, neonatal life, early life, pre-/post-menopause, puberty) of various dietary exposures may be vitally important in determining health beneficial effects, as epigenetic plasticity changes continually from conception to death [START_REF] Burdge | Nutrition in early life, and risk of cancer and metabolic disease: alternative endings in an epigenetic tale?[END_REF]. In principle; epigenetic changes occurring during embryonic development will have a much greater impact on the overall epigenetic status of the organism because, as they can be transmitted over consecutive mitotic divisions, alterations occurring in single embryonic stem cells will affect many more cells than those occurring in adult stem and /or somatic cells during postnatal development [START_REF] Aguilera | Epigenetics and environment: a complex relationship[END_REF]. Epigenetic plasticity further also depends on other processes such as chromosomal instability, telomere shortening, metabolic cycles, mitochondrial deteriorations, and oscillatory, circadian or seasonal rhythms of systemic hormone levels (hypothalamic-pituitary-adrenal (HPA) axis) [START_REF] Gluckman | Effect of in utero and early-life conditions on adult health and disease[END_REF][START_REF] Godfrey | Developmental origins of metabolic disease: life course and intergenerational perspectives[END_REF][START_REF]Moving AHEAD with an international human epigenome project[END_REF][START_REF] Plagemann | Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome[END_REF][START_REF] Burdge | Nutrition in early life, and risk of cancer and metabolic disease: alternative endings in an epigenetic tale?[END_REF][START_REF] De Assis | Timing of dietary estrogenic exposures and breast cancer risk[END_REF][START_REF] Guerrero-Bosagna | Epigenetic and phenotypic changes result from a continuous pre and post natal dietary exposure to phytoestrogens in an experimental population of mice[END_REF][START_REF] Hunter | We are what we eat. The link between diet, evolution and non-genetic inheritance[END_REF]. In addition to epigenetic imprinting during crucial periods of development, stochastic or genetically and environmentally triggered epigenomic changes (epimutations) occur day after day and accumulate over time, as maximal differences in DNA methylation profiles are observed in aged monozygotic twins with a history of non-shared environments [START_REF] Fraga | Epigenetic differences arise during the lifetime of monozygotic twins[END_REF][START_REF] Christensen | Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context[END_REF].

Concerning nutritional transgenerational inheritance there is increasing evidence in both plants and animals that, following nutritional intervention (caloric, iron and protein restriction, polyphenol-, folate-, micronutrient-, fat-or carbohydrate-rich diet), maternal diabetes, during pregnancy and lactation can affect the following generation(s) [START_REF] Kirk | Botanicals as epigenetic modulators for mechanisms contributing to development of metabolic syndrome[END_REF][START_REF] Youngson | Transgenerational epigenetic effects[END_REF][START_REF] Jirtle | Environmental epigenomics and disease susceptibility[END_REF][START_REF] Dolinoy | Environmental epigenomics in human health and disease[END_REF]219,[START_REF] Waterland | Methyl donor supplementation prevents transgenerational amplification of obesity[END_REF][START_REF] Waterland | Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases[END_REF]. Although it has long been thought that the epigenomic profile is wiped A c c e p t e d M a n u s c r i p t 18 clean in the embryo shortly after fertilization, with the exception of imprinted genes, methylation clearing is not complete after fertilization and on a global DNA level is reduced to 10% [START_REF] Surani | Mechanism of mouse germ cell specification: a genetic program regulating epigenetic reprogramming[END_REF][START_REF] Hajkova | Chromatin dynamics during epigenetic reprogramming in the mouse germ line[END_REF]. Alternatively, it can not be excluded that transgenerationally inherited nutritional effects may also depend on polycomb proteins [START_REF] Youngson | Transgenerational epigenetic effects[END_REF][START_REF] Chong | Heritable germline epimutation is not the same as transgenerational epigenetic inheritance[END_REF][START_REF] Blewitt | Dynamic Reprogramming of DNA Methylation at an Epigenetically Sensitive Allele in Mice[END_REF][START_REF] Bracken | Polycomb group proteins: navigators of lineage pathways led astray in cancer[END_REF], miRNA profiles [START_REF] Guil | DNA methylomes, histone codes and miRNAs: tying it all together[END_REF][START_REF] Li | Regulation of microRNAs by Natural Agents: An Emerging Field in Chemoprevention and Chemotherapy Research[END_REF] or epigenetic capacitor properties of hsp proteins [START_REF] Ruden | Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer[END_REF][START_REF] Sollars | Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution[END_REF][START_REF] Ruden | Drosophila nutrigenomics can provide clues to human gene-nutrient interactions[END_REF].

A next challenge will be to determine which adverse epigenomic marks are reversible by specific diets, drugs or lifestyle changes [START_REF] Godfrey | Developmental origins of metabolic disease: life course and intergenerational perspectives[END_REF][START_REF] Burdge | Nutrition, Epigenetics, and Developmental Plasticity: Implications for Understanding Human Diseas[END_REF][START_REF] Kirk | Botanicals as epigenetic modulators for mechanisms contributing to development of metabolic syndrome[END_REF][START_REF] Burdge | Nutrition in early life, and risk of cancer and metabolic disease: alternative endings in an epigenetic tale?[END_REF]. Numerous botanical species and plant parts contain a diverse array of polyphenolic phytochemicals which exert healthbeneficial effects in man by its anti-inflammatory, anti-oxidant, phytohormone, cardioprotective, cancer preventive and anti-bacterial properties, by maintaining immune homeostasis (hormesis) [START_REF] Dijsselbloem | Soy isoflavone phyto-pharmaceuticals in interleukin-6 affections: multi-purpose nutraceuticals at the crossroad of hormone replacement, anti-cancer and anti-inflammatory therapy[END_REF][START_REF] Surh | Cancer chemoprevention with dietary phytochemicals[END_REF]. Phytochemicals have also succesfully been applied for regenerative medicine and cancer stem cell therapy [START_REF] Kawasaki | Targeting cancer stem cells with phytochemicals[END_REF][START_REF] Blanpain | Epidermal homeostasis: a balancing act of stem cells in the skin[END_REF][START_REF] Crea | Targeting prostate cancer stem cells[END_REF][START_REF] Shytle | Oxidative stress of neural, hematopoietic, and stem cells: protection by natural compounds[END_REF][START_REF] Bickford | Nutraceuticals synergistically promote proliferation of human stem cells[END_REF][START_REF] Zhou | NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells[END_REF]. Oxidative stress and inflammatory damage plays an important role in epigenetic reprogramming of expression of cytokines, oncogenes and tumor suppressor genes, thereby setting up a ground for chronic inflammatory diseases and carcinogenesis [START_REF] Grivennikov | Inflammation and oncogenesis: a vicious connection[END_REF][START_REF] Aggarwal | Inflammation and cancer: how friendly is the relationship for cancer patients?[END_REF][START_REF] Aggarwal | Inflammation, a silent killer in cancer is not so silent![END_REF]. As such chemoprevention, the strategy to inhibit, retard, or even reverse the epigenetic stage of chronic inflammation is one of the most rational approaches to reduce the global burden of non communicable lifestyle diseases [START_REF] Anand | Cancer is a preventable disease that requires major lifestyle changes[END_REF][START_REF] Aggarwal | Inflammation and cancer: how friendly is the relationship for cancer patients?[END_REF][START_REF] Jirtle | Environmental epigenomics and disease susceptibility[END_REF]. "epigenetics" sheds a more realistic light on dietary studies, as longlife exposure at physiological concentrations can remodel the epigenome in a cumulative fashion by repetitive effects on the epigenetic machinery [START_REF] Manach | Polyphenols and prevention of cardiovascular diseases[END_REF][START_REF] Manach | Pharmacokinetics and metabolism of dietary flavonoids in humans[END_REF][START_REF] Manach | Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies[END_REF][START_REF] Manach | Polyphenols: food sources and bioavailability[END_REF][START_REF] Williamson | Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies[END_REF]. Particular attention needs to be given to natural compounds which can trigger opposite effects on HDAC/HAT/DNMT or histone (de)methylase (H(D)MT) depending on the concentration or cell type-specific metabolisation [START_REF] Link | Cancer chemoprevention by dietary polyphenols: Promising role for epigenetics[END_REF][START_REF] Folmer | Naturally occurring regulators of histone acetylation/deacetylation[END_REF]. It should also be stressed that it is not known whether all of them can be considered authentic epigenetic modifiers because it has not yet been demonstrated whether the epigenetic modifications that they induce are stable over time. Interestingly, even transient exposure to a specific dietary component can induce long-lasting epigenetic changes in the promoter of the NFB subunit p65, which acts as a master switch in inflammatory gene expression [START_REF] El-Osta | Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia[END_REF]. Alternatively, compounds may chemically interfere with histone mark interacting effector domains (such as chromo-, bromo-or tudor domains) [START_REF] Seet | Reading protein modifications with interaction domains[END_REF][START_REF] Zheng | Chemical regulation of epigenetic modifications: opportunities for new cancer therapy[END_REF][START_REF] Wigle | Screening for inhibitors of low-affinity epigenetic peptide-protein interactions: an AlphaScreen-based assay for antagonists of methyl-lysine binding proteins[END_REF].

However, one should be careful with interpretation of in vitro compound screenings or cofactor activity assays based on peptide-protein interactions, as this may not always represent true targets in vivo [START_REF] Altucci | Epigenetic therapies in haematological malignancies: searching for true targets[END_REF][START_REF] Pacholec | SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1[END_REF].

Besides specific interference of the diet with chromatin modifying enzymes and DNMTs at particular target genes, global epigenetic changes can also occur following biochemical metabolisation of dietary factors, which can deplete cellular pools of acetyl-CoA, NAD + and methyldonors, resulting in unbalanced DNA methylation and/or protein acetylation or methylation [START_REF] Vaquero | Calorie restriction and the exercise of chromatin[END_REF][START_REF] Ladurner | Chromatin places metabolism center stage[END_REF][START_REF] Imai | Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases[END_REF]. For example diets lacking in substrate or cofactors in methyldonormetabolism can contribute to DNA hypomethylation by impairing synthesis of SAM [START_REF] Chen | Regulation of homocysteine metabolism and methylation in human and mouse tissues[END_REF]. This methylation cycle is frequently cited to explain relations between diet and epigenetic changes [START_REF] Sharma | Mining literature for a comprehensive pathway analysis: a case study for retrieval of homocysteine related genes for genetic and epigenetic studies[END_REF][START_REF] Chiang | Effects of insulin and glucose on cellular metabolic fluxes in homocysteine transsulfuration, remethylation, Sadenosylmethionine synthesis, and global deoxyribonucleic acid methylation[END_REF]. However, even without nutritional deficiency of methyl groups, impaired synthesis of SAM and perturbed DNA methylation can happen when the need for the synthesis of the detoxification enzyme glutathione transferase (GSH) synthesis availability and SIRT activity [START_REF] Whittle | Sirtuins, nuclear hormone receptor acetylation and transcriptional regulation[END_REF]. Since SIRT activation has been linked to longevity (increased lifespan and healthy aging) and mimics a caloric restricted diet, SIRT activators such as resveratrol represent a major class of caloric mimetic epigenetic modulator phytochemicals which could reverse metabolic disease [START_REF] Imai | Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases[END_REF].

Conclusion

The phenotype of an individual is the result of complex gene-environment interactions in the current, past and ancestral environment, leading to lifelong remodelling of our epigenomes. In Hippocrates said already 25 centuries ago. As such, it will be a challenge for future antiinflammatory therapeutics and preventive cancer research to identify novel epigenetic targets which allow selective modulation of the inflammatory signaling network in the diseased tissue and/or microenvironment [START_REF] Surh | Cancer chemoprevention with dietary phytochemicals[END_REF][START_REF] Paul | Modulating TNF-alpha signaling with natural products[END_REF][START_REF] Rios | Inhibition of transcription factors by plant-derived compounds and their implications in inflammation and cancer[END_REF][START_REF] Deorukhkar | Back to basics: how natural products can provide the basis for new therapeutics[END_REF][START_REF] Khanna | Natural products as a gold mine for arthritis treatment[END_REF][START_REF] Bremner | Natural products as targeted modulators of the nuclear factor-kappaB pathway[END_REF][START_REF] Karin | The IKK NF-kappa B system: a treasure trove for drug development[END_REF]. Given several encouraging trials, prevention and therapy of age-and lifestyle-related diseases by individualised tailoring of optimal epigenetic diets or supplements are conceivable. However, these interventions will require intense efforts to unravel the complexity of these epigenetic, genetic and environment interactions. Another goal is to evaluate their potential reversibility with minimal side effects as diet components may reprogram malignant cells as well as the host immune system and HPA-axis depending on the bioavailability of the dietary compounds [START_REF] Burdge | Nutrition, Epigenetics, and Developmental Plasticity: Implications for Understanding Human Diseas[END_REF][START_REF] Ndlovu | Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells[END_REF][START_REF] Dijsselbloem | A critical role for p53 in the control of NF-kappaB-dependent gene expression in TLR4stimulated dendritic cells exposed to Genistein[END_REF][START_REF] Vanden Berghe | Attenuation of Mitogen-and Stress-Activated Protein Kinase-1-Driven Nuclear Factor-{kappa}B Gene Expression by Soy Isoflavones Does Not Require Estrogenic Activity[END_REF][START_REF] Manach | Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies[END_REF][START_REF] Williamson | Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies[END_REF] (See Figure 3). There is some concern that epigenetic therapy with dietary inhibitors of DNMT, HDAC, histon(de)methylases in longterm treatment setups may suffer from lack of specificity [START_REF] Mai | Epigenetic multiple ligands: mixed histone/protein methyltransferase, acetyltransferase, and class III deacetylase (sirtuin) inhibitors[END_REF][START_REF] Zheng | Chemical regulation of epigenetic modifications: opportunities for new cancer therapy[END_REF][START_REF] Altucci | Epigenetic therapies in haematological malignancies: searching for true targets[END_REF]. As such, the possible alternative is to combine nonselective A c c e p t e d M a n u s c r i p t 21 epigenetic therapies with more targeted approaches [START_REF] Hervouet | Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation[END_REF]. For example, combined treatment of specific transcription factor inhibitors and/or hormone receptor ligands with epigenetic drugs may trigger synergistic activities at subsets of inflammatory genes [START_REF] Perissi | Deconstructing repression: evolving models of co-repressor action[END_REF][START_REF] Hervouet | Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation[END_REF][START_REF] Biddie | Genome-wide mechanisms of nuclear receptor action[END_REF][START_REF] Fiskus | Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells[END_REF][START_REF] Croce | Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor[END_REF]. An excellent example of cooperation between a dietary vitamin A-derivative targeting a nuclear receptor and the HDAC inhibitor butyrate has been described in the treatment of acute promyelocytic leukemias [START_REF] Delage | Dietary manipulation of histone structure and function[END_REF]. Finally, microRNA and long ncRNA pathways also hold promise to join soon the arsenal of epigenetic combination therapies, as their target sequence specificity may bridge the gap between genetic and epigenetic changes [START_REF] Guil | DNA methylomes, histone codes and miRNAs: tying it all together[END_REF][START_REF] Tsai | Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes[END_REF][START_REF] Gupta | Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis[END_REF][START_REF] Santa | A large fraction of extragenic RNA pol II transcription sites overlap enhancers[END_REF]. In conclusion, studies are revealing a dazzling complexity in the mechanisms leading to dynamic alterations of the epigenome and the need of combination therapies targeting different chromatin modifiers, to reverse disease prone epigenetic alterations to preserve healthy aging.

Medical benefits of dietary compounds as epigenetic modulators, especially with respect to their chronic use as nutraceutical agents, will rely on our further understanding of their epigenetic effects during embryogenesis, early life, aging as well as through different generations.

A c c e p t e d M a n u s c r i p t

Interplay of inflammatory and metabolic stress pathways in nutritional epigenetic effects in lifestyle diseases. mut, mutation; SNP, single nucleotide polymorphism; miR, microRNA, ncRNA, noncoding RNA.

Figure 2

Working model illustrating crosstalk of inflammatory and metabolic stress pathways with epigenetic regulation in the nucleus. For example, transcription of the highly conserved IL6 gene promoter requires binding of activator protein AP1, CREB and nuclear factor NFB transcription factors in response to various stimuli [START_REF] Vanden Berghe | Dissociated glucocorticoids with anti-inflammatory potential repress interleukin-6 gene expression by a nuclear factor-kappaB-dependent mechanism[END_REF][START_REF] Vanden Berghe | p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-kappaB p65 transactivation mediated by tumor necrosis factor[END_REF], with strict stereospecific requirements for optimal cofactor recruitment, promoting a promoter enhanceosome model with multiple transcription factor/cofactor interactions, in which NFB is the primary trigger for IL6 gene induction in response to TNF. Inflammatory stimuli (i.e. TNF, virus, bacteria) or metabolic stress (including oxidative stresss, endoplasmic reticulum (ER) stress or unfolded protein response (UPR) stress, for example during obesity or malnutrition) can activate the IKK-complex, responsible for IB-phosphorylation, which allows NFB to translocate to the nucleus, following degradation of IB in the proteasome. IL6 gene expression also requires activation and recruitment of the mitogen-and stress-activated protein kinase-1 (MSK1) to elicit selective chromatin relaxation at the IL6 gene promoter, upon phosphorylation of NFB p65 S276 and histone H3 S10, followed by further CBP/p300 recruitment and HATdependent acetylation of the IL6 promoter enhanceosome/chromatin environment [START_REF] Vermeulen | Transcriptional activation of the NF-kappaB p65 subunit by mitogen-and stressactivated protein kinase-1 (MSK1)[END_REF].

Highly elevated expression levels of AP1 Fra1 and NFB in ER-deficient tumor cells increase chromatin accessibility (DNA hypersensitive sites) in the proximal IL6 gene promoter. Of particular interest, dietary anti-inflammatory phytochemicals such as soy polyphenol genistein [START_REF] Dijsselbloem | A critical role for p53 in the control of NF-kappaB-dependent gene expression in TLR4stimulated dendritic cells exposed to Genistein[END_REF][START_REF] Vanden Berghe | Attenuation of Mitogen-and Stress-Activated Protein Kinase-1-Driven Nuclear Factor-{kappa}B Gene Expression by Soy Isoflavones Does Not Require Estrogenic Activity[END_REF][START_REF] Dijsselbloem | Soy isoflavone phyto-pharmaceuticals in interleukin-6 affections: multi-purpose nutraceuticals at the crossroad of hormone replacement, anti-cancer and anti-inflammatory therapy[END_REF] and withanolide withaferin A [START_REF] Kaileh | Withaferin a strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity[END_REF] are able to silence the highly promiscuous IL6 promoter nucleosome configuration by lowering the cellular amounts of Fra1 and NFB activity, concomitantly with decreased histone H3 phosphoacetylation levels and increased DNA methylation [START_REF] Ndlovu | Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells[END_REF][START_REF] Dijsselbloem | A critical role for p53 in the control of NF-kappaB-dependent gene expression in TLR4stimulated dendritic cells exposed to Genistein[END_REF][START_REF] Vanden Berghe | Attenuation of Mitogen-and Stress-Activated Protein Kinase-1-Driven Nuclear Factor-{kappa}B Gene Expression by Soy Isoflavones Does Not Require Estrogenic Activity[END_REF].

A c c e p t e d M a n u s c r i p t 8 RNAs

 8 such as snoRNAs[START_REF] Taft | Noncoding RNAs: regulators of disease[END_REF][START_REF] Taft | Tiny RNAs associated with transcription start sites in animals[END_REF][START_REF] Mattick | A global view of genomic information -moving beyond the gene and the master regulator[END_REF]. These RNAs (including those derived from introns) appear to comprise a hidden layer of internal signals that control various levels of gene expression in physiology and development, including chromatin architecture/epigenetic memory,

  Members of the NFκB family of dimeric transcription factors (TF) regulate expression of a large number of genes involved in immune responses, inflammation, metabolic stress, cell survival, and cancer. NFκB family TF are rapidly activated in response to various stimuli, including cytokines, infectious agents, overnutrition (metabolic stress, endoplasmic reticulum stress) or danger signals (bacteria, viruses, chemicals, pathogen associated molecular patterns (PAMPs), danger associated molecular patterns (DAMPs), and radiation-induced DNA double-strand breaks. In nonstimulated cells, some NFκB TFs are bound to inhibitory (I)κB proteins and are thereby sequestered in the cytoplasm. Activation leads to phosphorylation of IκB proteins and their subsequent recognition by ubiquitinating enzymes. The resulting proteasomal degradation of IκB proteins liberates NFκB TF, which translocate to the nucleus to drive expression of target genes. Two protein kinases with a high degree of sequence similarity, IκB kinase (IKK)α and IKKβ, mediate phosphorylation of IκB proteins and represent a convergence point for most signal transduction pathways leading to NFκB activation. Most of the IKKα and IKKβ molecules in the cell are part of IKK complexes that also contain a regulatory subunit called IKKγ or NFκB-essential modulator (NEMO). Several years ago, two IKK-related kinases,called IKKε and TBK1 (TANK-binding kinase), were identified that exhibit structural similarity to IKKα and IKKβ[START_REF] Chau | Are the IKKs and IKK-related kinases TBK1 and IKK-epsilon similarly activated?[END_REF]. Together, the IKKs and IKK-related kinases are instrumental for inducible activation of the host defense system and controlling metabolic stress[START_REF] Olefsky | IKKepsilon: a bridge between obesity and inflammation[END_REF][START_REF] Hotamisligil | Endoplasmic reticulum stress and the inflammatory basis of metabolic disease[END_REF][START_REF] Ghosh | New regulators of NF-kappaB in inflammation[END_REF][START_REF] Chiang | The protein kinase IKKepsilon regulates energy balance in obese mice[END_REF][START_REF] Perkins | Integrating cell-signaling pathways with NF-kappaB and IKK function[END_REF]. Alternative to IKK, various additional kinases have been identified which modulate transcriptional nuclear activity of NFκB, including mitogen-and stress-activated protein kinase (MSK), protein kinase (PK)Ac, phosphoinositide 3-kinases A c c e p t e d M a n u s c r i p t 10 PI3K and AKT[START_REF] Chen | Shaping the nuclear action of NF-kappaB[END_REF][START_REF] Viatour | Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation[END_REF][START_REF] Vermeulen | The versatile role of MSKs in transcriptional regulation[END_REF][START_REF] Vermeulen | Transcriptional activation of the NF-kappaB p65 subunit by mitogen-and stressactivated protein kinase-1 (MSK1)[END_REF][START_REF] Edmunds | Cell signaling. Protein kinases seek close encounters with active genes[END_REF]. Furthermore, constitutive activity of NFκB/IKK has been observed in many cancer cells, inflammatory disorders, obesity and insulin resistance[102, 103, 105-108, 112, 117-119]. During obesity, the organism needs to adapt to and function under chronic exposure to high energy and nutrient intake. To cope with these challenges, the cell has developed the endoplasmic reticulum (ER) as a key nutrition sensor of cellular metabolic parameters (hyperglycemia, fatty acid overload, hypoglycemia, oxidative stress), which participates in viruatlly all anabolic and catabolic branches. Failure of the ER"s adaptive capacity results in activation of the unfolded protein resonse (UPR), which intersects with many different inflammatory and stress signaling pathways at the crossroad of inflammation, cancer and metabolic disease[START_REF] Tennant | Targeting metabolic transformation for cancer therapy[END_REF][START_REF] Hotamisligil | Endoplasmic reticulum stress and the inflammatory basis of metabolic disease[END_REF][START_REF] Mandl | Endoplasmic reticulum: nutrient sensor in physiology and pathology[END_REF].Gene-specific mechanisms operate at the level of individual genes and gene subsets.Induction of inflammatory transcriptional responses is orchestrated by many transcription factors and extragenic noncoding RNAs acting on inflammatory enhancers consistent with the complexity of the response[START_REF] Santa | The histone H3 lysine-27 demethylase JMJD3 links inflammation to inhibition of polycombmediated gene silencing[END_REF][START_REF] Ghisletti | Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages[END_REF][START_REF] Ghisletti | Parallel SUMOylation-dependent pathways mediate gene-and signal-specific transrepression by LXRs and PPARgamma[END_REF][START_REF] Smale | Seq-ing LPS-induced enhancers[END_REF][START_REF] Xu | Transcriptional competence and the active marking of tissue-specific enhancers by defined transcription factors in embryonic and induced pluripotent stem cells[END_REF]. Controlled expression of cytokine genes is an essential component of an immune response and is crucial for homeostasis. In order to generate an appropriate response to metabolic stress or an infectious condition, the type of cytokine, as well as the cell type, dose range and the kinetics of its expression are of critical importance[START_REF] Natoli | Interactions of NF-kappaB with chromatin: the art of being at the right place at the right time[END_REF][START_REF] Hager | Transcription dynamics[END_REF][START_REF] Sung | Sustained oscillations of NF-kappaB produce distinct genome scanning and gene expression profiles[END_REF]. The NFκB family TF has a crucial role in rapid responses to metabolic stress and pathogens (innate immunity), as well as in development and differentiation of immune cells (acquired immunity). Although quite a number of genes contain NFκB-responsive elements in their regulatory regions, their expression pattern can significantly vary from both a kinetic and quantitative point of view[START_REF] Vanden Berghe | Keeping up NF-kappaB appearances: epigenetic control of immunity or inflammation-triggered epigenetics[END_REF][START_REF] Medzhitov | Transcriptional control of the inflammatory response[END_REF][START_REF] Ghosh | New regulators of NF-kappaB in inflammation[END_REF][START_REF] Perkins | Integrating cell-signaling pathways with NF-kappaB and IKK function[END_REF][START_REF] Natoli | Interactions of NF-kappaB with chromatin: the art of being at the right place at the right time[END_REF][START_REF] Ramirez-Carrozzi | A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling[END_REF][START_REF] O'dea | The regulatory logic of the NF-kappaB signaling system[END_REF][START_REF] Werner | Stimulus specificity of gene expression programs determined by temporal control of IKK activity[END_REF][START_REF] Hayden | Shared principles in NF-kappaB signaling[END_REF]. At the transcription level, selectivity is conferred by the expression of specific NFκB subunits and their respective posttranslational modifications, and by combinatorial interactions between NFκB and other transcription enhancer factors (for example interferon regulatory factor (IRF)3, activating transcription factor (ATF)3, cAMP response element-binding protein CREB, CCAATenhancer binding protein C/EBP, activator protein (AP)1 (i.e. jun, fos, Fra1), Sp1, Stat3, PU.1)[START_REF] Chen | Shaping the nuclear action of NF-kappaB[END_REF][START_REF] Ghisletti | Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages[END_REF][START_REF] Vanden Berghe | The nuclear factor-kappaB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter[END_REF]. In addition to NFB, AP1 TF are closely involved in inflammatory disease and cancer invasive gene expression programs[START_REF] Ndlovu | Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells[END_REF][START_REF] Eferl | AP-1: a double-edged sword in tumorigenesis[END_REF]. Inflammatory transcription factors can be divided into different categories on the basis of their mode of activation and function[START_REF] Medzhitov | Transcriptional control of the inflammatory response[END_REF]. Primary response transcription factors are constitutively expressed by many celltypes in the cytoplasm and are activated by signal-dependent posttranslational modifications, which involves their nuclear translocation, such as NFκB, IRF, CREB. This TF are mainly responsible for the primary phase of gene induction and integrate signals from

  A c c e p t e d M a n u s c r i p t 11 diverse signaling pathways which can amplify or terminate signal-dependent transcription factor activation. Another class TF requires de novo synthesis following inflammatory stimulation, for example C/EBP. Most are constitutively nuclear and regulate secondary waves of gene expression. A third class of constitutively nuclear TF are expressed in a celltype-specific and differentiation-dependent manner, such as Runx, PU.1, IRF8, AP1, C/EBP[START_REF] Ghisletti | Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages[END_REF][START_REF] Ramirez-Carrozzi | A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling[END_REF]. They establish cell type-specific patterns of gene expression and are involved in chromatin remodelling during cell differentiation and organization of higher-order chromatin structure and chromosomal domains. The transcription factors of these TF categories do not act independently, but function coordinately to control the inflammatory transcriptional response. Upon combining datasets of expression profiling of inflammatory genes and in silico motif scanning of promoters of these genes they can define gene clusters that are coordinately regulated and the transcription factors that are likely to control their expression[START_REF] Vanden Berghe | Keeping up NF-kappaB appearances: epigenetic control of immunity or inflammation-triggered epigenetics[END_REF][START_REF] Medzhitov | Transcriptional control of the inflammatory response[END_REF][START_REF] Ghosh | New regulators of NF-kappaB in inflammation[END_REF][START_REF] Chen | Shaping the nuclear action of NF-kappaB[END_REF][START_REF] Perkins | Integrating cell-signaling pathways with NF-kappaB and IKK function[END_REF][START_REF] Natoli | Interactions of NF-kappaB with chromatin: the art of being at the right place at the right time[END_REF][START_REF] Ramirez-Carrozzi | A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling[END_REF][START_REF] O'dea | The regulatory logic of the NF-kappaB signaling system[END_REF][START_REF] Werner | Stimulus specificity of gene expression programs determined by temporal control of IKK activity[END_REF][START_REF] Hayden | Shared principles in NF-kappaB signaling[END_REF]. Since TF bind very poorly or not at all to nucleosomal DNA, their activation is coordinated to recruitment of ATP-dependent chromatin-remodeling factors (swith/sucrose non fermentable (SWI/SNF), Brahma (Brm), brahma-related gene, (Brg1)), histone-enzyme complexes such as kinases (IKK, MSK, ataxia telangiectasia mutated (ATM), AKT, PI3K), poly(ADP-ribose) polymerase (PARP), methylases (EZH2, coactivatorassociated arginine methyltransferase (CARM)1, protein arginine methyltransferases (PRMT)), demethylases (lysine specific demethylase (LSD)1, Jumonji C family histone demethylase (JMJD)3), prolyl isomerase (PIN1), acetylases (p300, CREB binding protein (CBP), p300/CBP associated factor (p/CAF)), deacetylases (HDAC, SIRT) and DNMTs[START_REF] Vanden Berghe | Keeping up NF-kappaB appearances: epigenetic control of immunity or inflammation-triggered epigenetics[END_REF][START_REF] Perissi | Deconstructing repression: evolving models of co-repressor action[END_REF][START_REF] Ghosh | New regulators of NF-kappaB in inflammation[END_REF][START_REF] Vermeulen | The versatile role of MSKs in transcriptional regulation[END_REF][START_REF] Rosenfeld | Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response[END_REF][START_REF] Dong | Repression of gene expression by unphosphorylated NF-kappaB p65 through epigenetic mechanisms[END_REF]. Parallel posttranslational modifications (phosphorylation, acetylation, methylation, ribosylation, sumoylation, ubiquitination) of histone and non-histone TF and cofactor complexes allow formation of dynamic enhanceosome complexes which establish a distinct chromatin structure. These epigenetic settings are the ultimate integration sites of both environmental and differentiative inputs, determining proper expression of each inflammatory gene[START_REF] Vanden Berghe | Keeping up NF-kappaB appearances: epigenetic control of immunity or inflammation-triggered epigenetics[END_REF][START_REF] Ghosh | New regulators of NF-kappaB in inflammation[END_REF][START_REF] Hayden | Shared principles in NF-kappaB signaling[END_REF][START_REF] Natoli | Shaping alternative NF-kappaB-dependent gene expression programs: new clues to specificity[END_REF][START_REF] Ford | The transcriptional code of human IFN-beta gene expression[END_REF].Further investigation of epigenetic regulation of inflammatory genes, revealed different different subclasses according to chromatin activation mode and gene expression profile[START_REF] Ramirez-Carrozzi | A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling[END_REF] 139]. A major class of primary response genes is characterized by CpG-island promoters, which facilitate promiscuous induction from constitutively active chromatin without a requirement for SWI/SNF nucleosome remodeling complexes. The low nucleosome occupancy at promoters in this class can be attributed to the assembly of CpG-islands into unstable nucleosomes, which may lead to SWI/SNF independence. Another major class A c c e p t e d M a n u s c r i p t 12 consists of non-CpG-island promoters that assemble into stable nucleosomes, resulting in SWI/SNF dependence and the requirement for transcription factors that promote selective nucleosome remodeling. Some inflammatory stimuli such as TNF, exhibit a strong bias toward activation of SWI/SNF-independent CpG-island genes. In contrast interferon (IFN) preferentially activates SWI/SNF-dependent non-CpG-island promoters. Interestingly, by activating a diverse set of transcription factors, Toll like receptors (TLR) induce both classes and others for an optimal response to PAMPs and DAMPs[START_REF] Ramirez-Carrozzi | A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling[END_REF]. Remarkably, DNA methylation of IKK, IB and RelB promoters[START_REF] Puto | Daxx represses RelB target promoters via DNA methyltransferase recruitment and DNA hypermethylation[END_REF][START_REF] Maeda | Epigenetic inactivation of IkappaB Kinase-alpha in oral carcinomas and tumor progression[END_REF][START_REF] O'gorman | Regulation of NF-{kappa}B responses by epigenetic suppression of I{kappa}B{alpha} expression in HCT116 intestinal epithelial cells[END_REF] adds another regulatory control level which can act as transcription memory for repetitive pulsatile inflammatory exposures (endotoxin sensitization versus tolerance)[START_REF] Puto | Daxx represses RelB target promoters via DNA methyltransferase recruitment and DNA hypermethylation[END_REF][START_REF] Ashall | Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription[END_REF][START_REF] El Gazzar | Chromatinspecific remodeling by HMGB1 and linker histone H1 silences proinflammatory genes during endotoxin tolerance[END_REF][START_REF] El Gazzar | Epigenetic silencing of tumor necrosis factor alpha during endotoxin tolerance[END_REF][START_REF] El-Osta | Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia[END_REF].Chronic inflammatory disorders and epimutations: cause or consequence?Since inflammatory gene expression dynamics is highly dependent on epigenetic control mechanisms[START_REF] Vanden Berghe | Keeping up NF-kappaB appearances: epigenetic control of immunity or inflammation-triggered epigenetics[END_REF][START_REF] Medzhitov | Transcriptional control of the inflammatory response[END_REF][START_REF] Messi | Memory and flexibility of cytokine gene expression as separable properties of human T(H)1 and T(H)2 lymphocytes[END_REF][START_REF] Santa | The histone H3 lysine-27 demethylase JMJD3 links inflammation to inhibition of polycombmediated gene silencing[END_REF][START_REF] Natoli | Interactions of NF-kappaB with chromatin: the art of being at the right place at the right time[END_REF][START_REF] Natoli | Shaping alternative NF-kappaB-dependent gene expression programs: new clues to specificity[END_REF], we have compared chromatin organization in weak or strong inflammatory cancer cell types with inducible or constitutive interleukin (IL)6 gene expression patterns. Upon investigation of autocrine IL6 gene expression production in aggressive myeloma cells or metastatic breast cancer cells, we observed euchromatin-like properties and highly accessible chromatin at the IL6 gene promoter[START_REF] Ndlovu | Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells[END_REF][START_REF] Gerlo | Transcriptional regulation of autocrine IL-6 expression in multiple myeloma cells[END_REF]. Furthermore, recruitment of CBP/p300 acetylases and MSK kinase seems to prevent heterochromatinisation and recruitment of heterochromatin protein (HP)1 upon phosphacetylation of transcription factor and histone components[START_REF] Vermeulen | The versatile role of MSKs in transcriptional regulation[END_REF][START_REF] Vermeulen | Transcriptional activation of the NF-kappaB p65 subunit by mitogen-and stressactivated protein kinase-1 (MSK1)[END_REF][START_REF] Vanden Berghe | The nuclear factor-kappaB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter[END_REF][START_REF] Ndlovu | Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells[END_REF][START_REF] Boeke | Phosphorylation of SU(VAR)3-9 by the chromosomal kinase JIL-1[END_REF] (See Figure2). Interestingly, promoter binding activity of Sp1 and AP1 Fra1 are responsible for priming IL6 promoter chromatin relaxation, which further promotes binding of NFκB transcription factors and chromatin opening for maximal expression levels[START_REF] Ndlovu | Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells[END_REF][START_REF] Gerlo | Transcriptional regulation of autocrine IL-6 expression in multiple myeloma cells[END_REF]. Interestingly, complementation of low invasive cancer cells with Fra1 seems to convert the promoter chromatin architecture in a highly accessible chromatin configuration. Reciprocally, highly accessible chromatin in invasive cancer cells can be silenced with anti-inflammatory phytochemicals, or following silencing of AP1/NFκB transcription factors, demonstrating reversible epigenetic changes towards a less aggressive phenotype[START_REF] Ndlovu | Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells[END_REF][START_REF] Dijsselbloem | A critical role for p53 in the control of NF-kappaB-dependent gene expression in TLR4stimulated dendritic cells exposed to Genistein[END_REF][START_REF] Vanden Berghe | Attenuation of Mitogen-and Stress-Activated Protein Kinase-1-Driven Nuclear Factor-{kappa}B Gene Expression by Soy Isoflavones Does Not Require Estrogenic Activity[END_REF]. Along the same line, we and others observed DNA hypermethylation at the IL6 gene promoter in cancer cells with low NFκB/AP1 activity and inducible IL6 gene expression, as compared to DNA hypomethylation in cancer cells with hyperactivated NFκB/AP1 transcription factors and elevated constitutive IL6 gene expression ([START_REF] Armenante | Repression of the IL-6 gene is associated with hypermethylation[END_REF][START_REF] Dandrea | MeCP2/H3meK9 are involved in IL-6 gene silencing in pancreatic adenocarcinoma cell lines[END_REF] and Figure2). Similarly, p53 knockout cells reveal defects in genomic imprinting and DNA methylation regulation[START_REF] Aaltonen | Cross-section-constrained top-quark mass measurement from dilepton events at the Tevatron[END_REF] As such, this demonstrates that A c c e p t e d M a n u s c r i p t 13 inflammatory signaling and transcription factors are able to rewire epigenetic settings and amplify gene expression in an autocrine fashion [46, 154]. As another example, DNA methylation of the NFκB responsive element in the Fas (CD95, Apo-1, TNFRSF6) gene

A c c e p t e d M a n u s c r i p t 14 which

 14 in turn augments the state of inflammation. In addition, reactive nitrogen intermediates such as NO and ROS, indirectly also modulate activity of epigenetic machinery which finally

A c c e p t e d M a n u s c r i p t 16 mothers

 16 who were severely undernourished during the first trimester of their pregnancies in 1944-1945, as compared to those born to mothers whose pregnancies were more advanced at

A c c e p t e d M a n u s c r i p t 17 JMJD3

 17 demethylase was demonstrated to regulate monocyte/macrophage transdifferentiation programs, illustrating that developmental programs are plastic and monocyte lineage

A c c e p t e d M a n u s c r i p t 19 the

 19 following mechanisms, either covalent trapping of DNMT through incorporation into DNA (i.e. nucleoside analogues decitabine, 5-azacytidine), non-covalent blocking of DNMT catalytic active site (i.e. EGCG, parthenolide), interruption of binding site of DNMT to DNA (i.e. procaine), degradation of DNMT (i.e; decitabine), or suppression of DNMT expression (i.e. miRNAs). Furthermore, a number of natural compounds act as multifunctional ligands by simultaneously acting on nuclear hormone receptors and changing activity of histone modifying enzymes and DNMTs[START_REF] Mai | Epigenetic multiple ligands: mixed histone/protein methyltransferase, acetyltransferase, and class III deacetylase (sirtuin) inhibitors[END_REF][START_REF] Kuniyasu | The Roles of Dietary PPARgamma Ligands for Metastasis in Colorectal Cancer[END_REF][START_REF] Denison | Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals[END_REF][START_REF] Darbre | Environmental oestrogens and breast cancer: evidence for combined involvement of dietary, household and cosmetic xenoestrogens[END_REF][START_REF] Newbold | Environmental estrogens and obesity[END_REF]. Of special note, although health protective antioxidant or anti-inflammatory effects of dietary factors and extracts have frequently been demonstrated in in vitro experiments at concentrations which can never be achieved in vivo,

A c c e p t e d M a n u s c r i p t 20 increases [ 299

 20299 ]. Diets or nutritional compounds which affect energy metabolism or mitochondrial respiration can have global epigenetic effects upon changes in NAD +

  recent years, several studies have demonstrated that disruption of epigenetic mechanisms can alter immune function and and that epimutations not only contribute to various cancers but also to the development of diabetes, allergy, CVD and rheumatoid arthritis. Various replication-dependent and -independent epigenetic mechanisms are involved in developmental programming, lifelong recording of environmental changes and transmitting transgenerational effects. It is likely that understanding and manipulating the epigenome, a potentially reversible source of biological variation, has great potential in chemoprevention or stabilization of chronic inflammatory disorders. Much attention is currently focusing on modulating hyper/hypomethylation of key inflammatory genes by dietary factors as an effective approach to cure or protect against inflammatory disease[32-41, 213, 282]. In this respect, "Let food be your epigenetic medicine" could represent a novel interpretation of what

Figure 3 .

 3 Figure 3.Flowchart which summarizes the complex and multilayered regulation of nutritional epigenetic effects.

A c c e p t e d M a n u s c r i p t

Figure 1 Page 44 of 45 A c c e p t e d M a n u s c r i p t

 145 Figure 1

Figure 2

 2 Figure 2

Table 1 .

 1 Overview of nutritional epigenetic effects by dietary phytochemicals (summarized from[32-41, 213, 282] and references included). Suffix I, inhibitor; suffix a, activator, for example HDACi, HDAC inhibitor, or SIRTa, SIRT activator

	Bioactive Phytochemical	Natural Source	Disease Target	Epigenetic mechanism	In vitro / In vivo	Target genes / microRNAs
	3,3-	Broccoli	Cancer	Decreased HDAC	In vitro / in vivo	COX2
	diindolylmethane			levels
	6-methoxy-2E,9E-	Ginger	Cancer	HDACi	In vitro
	humuladien-8-one
	Allylmercaptan	Garlic	Cancer	HDACi	In vitro/in vivo	P21/WAF
	Anacardic Acid	Cashew nuts	Cancer, Leukemia	HATi	In vitro
	Apigenin	Parsley, celery	Cancer	DNMTi	In vitro
	Betanin	Beetroot red	Cancer	DNMTi	In vitro
	Biochanin A	Soy	Cancer	DNMTi	In vitro / in vivo
				HDACi	Daphnia
	Butyryc acid	Fermentation	Cancer	HDACi	In vitro / In vivo
		dietary fibers
	Caffeic acid	Coffea	Cancer	DNMTi	In vitro	RAR, CDKN2A
			Inflammation	HDACi
			Energy metabolism
	Catechin	Green tea	Cancer	DNMTi	In vitro	RAR
			Lymphocytes	HATi
	Chlorogenic acid	Coffea	Cancer	DNMTi	In vitro	RAR, CDKN2A
				HDACi
	Coumaric acid	Cinnamon	Cancer	DNMTi	In vitro / in vivo
	Cinnamic acid			HDACi
	Coumarin	Melilotus	Cancer, Leukemia,	SIRTi	In vitro
	analogues	officinalis		p53 acetylation
	Dihydrocoumarin	(Sweet clover)
	Curcumin	Turmeric	Crohn's Disease,	DNMTi	In vitro / In vivo	GATA4, EOMES,
		(Curcuma	Ulcerative colitis	HATi	Plasmodium	GZMB, PRF1
		longa L.)	Inflammatory disease	HDACi	falciparum,
			Cancer, Leukemia Neurodegeneration Alzheimer Diabetes Heart Failure Epilepsy		Herpes Virus Mouse Rat	Up: miR-22, miR-34a, miR-24, miR-181a, miR-21,miR-181b, miR-27a Down: miR-199a, miR-510, miR-196a, miR-7,
						miR-15b,
						miR-195, miR-374,
						miR-98
	Cyanidin	Berries,	Cancer	DNMTi	In vitro
		Grapes
	Daidzein	Soy	Cancer	DNMTi	In vitro
				SIRTa
	Diallyl disulfide	Garlic	Inflammatory disease	HDACi	In vitro / in vivo	p21/WAF
			Cancer		rat
	Ellagic Acids	Berries	Cancer	DNMTi	In vitro
	Epicatechin	Apples, Cocoa,	Inflammatory	DNMTi	In vitro
		Green and	disease, lymphocytes	HATi
		black tea	Cancer
			CVD
	Epicatechin	Green tea	Cancer	DNMTi	In vitro
	gallate		Lymphocytes	HATi
	Epigallocatechin	Green tea	Cancer	DNMTi	In vitro
			Lymphocytes	HATi
	Epigallocatechin	Green tea	Inflammatory disease	DNMTi	In vitro / In vivo	RAR, MGMT, MLH1,
	3-gallate (EGCG)		Parkinson	HDACi	Agouti	CDKN2A, RECK, TERT,
			Cancer, Leukemia	HMTi	Mouse/Human	RXR, CDX2, GSTP1,
						WIF1, NFkB, IL6, Bmi1,
			CVD			Ezh2, Suz12
						Up : let-7, miR-16,

Acknowledgements

This research is partially financial supported by FP7-KBBE-2008-2B grant FLAVIOLA ("Targeted delivery of dietary flavanol for optimal human cell function: Effects on cardiovascular health (www.flaviola.org)), Research Grant from the Multiple Myeloma Research Foundation (MMRF) and Interuniversity Attraction Poles (IAP) P6/18. We regret that not all literature could be cited appropriately because of space constraints and we apologize to those authors whose original work is not mentioned.