**1. Introduction**

For many years it's been widely known by scientists that, despite possessing the same DNA sequence, not all genes can be active in all cells within an organism all of the time. It is through the regulation of genes that we are able to see phenotypic differences between cells with identical genotypes. In the late 1930's, Conrad Waddington introduced the term 'epigenetic landscape' to provide a metaphor for the cellular mechanisms leading to this regulation [1]. These regulatory, or epigenetic, patterns can be seen to persistently influence gene expression levels through cell division. Hence, epigenetics involves the study of marks and mechanisms that control gene expression in a mitotically and potentially meiotically heritable manner [2].

One such mechanism is DNA methylation (or more specifically cytosine methylation), an important epigenetic modification. DNA methylation, in conjunction with histone modifica‐ tions, remodeling complexes and non-coding RNAs, plays a vital role in regulating genome dynamics. In combination with these other modifications, DNA methylation can control the

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accessibility of the underlying DNA to the transcriptional machinery through the modulation of chromatin density. As a result DNA methylation is involved in a diverse range of processes including embryogenesis, genomic imprinting, cellular differentiation, DNA protein interac‐ tions and gene regulation [3].

In mammalian genomes, DNA methylation occurs almost exclusively at palindromic CpG dinucleotides. CpG dinucleotides are found throughout the genome but are significantly depleted (21% of that expected in the human genome [4]) in comparison to other dinucleotide combinations. This is due to the hypermutability of methylated cytosines [5] where sponta‐ neous deamination to thymine occurs. However as a result of chance or potentially due to their functional importance, a minority of CpGs are maintained against this loss.

The surviving CpGs are often found at a high density in localised genomic regions termed CpG islands (CGIs) [3]. Unlike the majority of CpGs, these regions, of approximately 1kb in length (though different algorithms produce different CGI predictions [6]), are largely unmethylated and have been found to overlap the promoter regions of 60–70% of all human genes, representing all constitutively expressed genes and approximately 40% of those displaying tissue specific expression patterns [7, 8]. Unmethylated CGIs are able to recruit CpG binding proteins such as Cfp1 [9], these in turn lead to the modification of histone tails [10] and the formation of permissive chromatin domains, potentially enabling the initiation of transcription [11]. In contrast, methylated CGIs are associated with gene silencing. This silencing can occur via various routes such as inhibiting the recruitment of DNA binding proteins from their target sites [12] or alternatively through the recruitment of methyl-CpGbinding domain (MBD) proteins that in turn recruit histone modifying complexes to the methylated sites [13].

Whilst methylation changes at CGIs is perhaps the most studied region, methylation occurs in other genomic locations as well. CpG island shores represent regions of lower CpG density flanking a CGI. They are generally defined as reaching 2kb upstream and downstream of an island. It has been found that most tissue specific methylation occurs in these shore regions rather than the islands [14, 15]. Additionally, high levels of DNA methylation can be found in repetitive genomic regions. Rather than directly regulating the transcriptional potential of a gene, this methylation is seen to prevent chromosomal instability [16-18].

Although DNA methylation is largely found in the CpG dinucleotide, it has also been reported in humans and mouse at CHG and CHH sites [19, 20]. In comparison with a methylated CpG site, methylated non-CpG sites display a much lower level of methylation within a cell population [21] and show lower conservation between cell lines [22]. The mechanisms and functionality of non-CpG methylation are currently unclear but the levels appear to decrease during differentiation whilst being restored in induced pluripotent stem cells. This potentially suggests a role in the origin and maintenance of the pluripotent state [19, 23, 24].

DNA methylation changes have been associated with numerous conditions. Many cancers have shown hypomethylation at repetitive sequences thus promoting chromosomal instabil‐ ity. Examples include the LINE repeat L1 in a range of tumours [25] and satellite repeats ALRα and SATR1 in peripheral nerve sheath tumours [26]. Hypomethylation at specific promoters can lead to aberrant expression of oncogenes, whilst in contrast hypermethylation at specific island or shore sites can lead to transcriptional inactivation of genes involved in pathways such as DNA repair and apoptosis [2, 13]. Neurological disorders such as Alzheim‐ er's and Multiple sclerosis have been associated with aberrant DNA methylation as have autoimmune diseases such as ICF syndrome and rheumatoid arthritis [2].
