## 2 Epigenetic Modulation  
Epigenetics can be identified as the ensemble of the genome modifications that are hereditable, reversible and that do not involve the alteration of the nucleotide sequence [20]. Epigenetic modifications affect gene expression and protein level, so that they are involved in normal cell growth and development, cell commitment, and differentiation [21]. The tridimensional organization of chromatin is a crucial epigenetic factor in the regulation of gene expression. Chromatin is essentially organized in nucleosomes; each nucleosome consists of DNA wrapped around an octamer of globular proteins named histones (H), more precisely one H3-H4 tetramer and two H2A-H2B-dimers. Chromatin is a complex and extremely dynamic structure that can be found either in a highly condensed inactive state, heterochromatin, in which genes are switched off and cannot be expressed, or in a less condensed state known as euchromatin, which is more accessible to transcriptional factors due to its open conformation that allows gene expression [22]. The main epigenetic modifications involve DNA methylation, histone modifications and microRNA regulation and expression (reviewed in [21; 22; 23; 24; 25; 26]). These epigenetic mechanisms are indeed able to modify the chromatin organization by inducing or preventing gene expression [27]. Since DNA methylation has been found mostly in promoter regions of silenced genes, it has been associated with transcriptional repression, whereas CpG islands (sites of transcription initiation) are usually unmethylated in tissue-specific and in \"housekeeping\" genes, which are constitutively expressed in all tissue. The enzymes involved in the methylation process are DNA methyltransferases (DNMT) [28]. Post-translational histone modifications are involved in chromatin remodeling. The most well-known modifications are methylation and acetylation of lysine residues on histone H3 and H4 and acetylation of histone H2A and H2B (reviewed in [24]). Histone acetyltransferase (HATs) and histone deacetylases (HDACs) catalyze the acetylation and the deacetylation of histone tails residues, respectively. Active regions of chromatin are therefore characterized by high level of unmethylated DNA and acetylated histones; these reversible modifications ensure the expression of specific sets of genes depending on the developmental, metabolic, and environmental state of the cell [29; 30; 31].  
Many epigenetic abnormalities are associated with the development of a great range of diseases, including neurological, autoimmune, cardiovascular, infectious, aging, and cancer. Cancer can be defined as a multistep process characterized by the accumulation of both genetic and epigenetic errors that transform a healthy cell into a tumor cell [27]. The global DNA methylation and histone acetylation profiles of cancer cells show a targeted perturbation, characterized by a region-specific pattern, leading to a limited differentiation. The global hypomethyllation occurs in gene bodies and within repetitive sequences whereas a specific hypermethylation can be found in the promoter region of tumor suppressor genes [32; 33]. The epigenetic changes, when not consequent to a mutation on an epigenetic modulator, are dynamic, transient, and reversible. Therefore, epigenetic modulators have been considered new potential target for cancer treatment and an increasing number of small molecules acting upon epigenetic regulators have been approved by FDA in the last years [34; 35; 36].