**1. Introduction**

Epigenetics is defined as the investigation on gene expression alterations heritable to next generations caused by nongenetic but heritable cellular memory other than DNA sequence variations [1]. The epigenetic memories including dynamic base modifications (DNA methylation/ demethylation), histone modifications, chromatin architecture, and noncoding RNAs maintain all the biological processes in the programmed tracks. Any aberrant alterations could lead to development of abnormality and initiation of diseases such as neurological disorders and cancers as reviewed in [2–8]. A micro-event in base modification could lead to strong "earthquake" in the signaling pathways and the consequent alteration of organism phenotypes, even diseases. The most extensively studied modifications are methylation and demethylation of 5-cytosine (5-C).

replication, making the enzyme indispensable for dividing progenitor cells [29, 39, 40]. This is supported by the finding that DNMT1 has higher affinity to hemimethylated DNA [41, 42] and that gene knockout of Dnmt1 in the central nervous system leads to lethal in mice [43]. While Dnmt1 deletion in all dividing somatic cells is also lethal [43–47], mouse embryonic stem cells are viable, despite the resulting global loss of DNA methylation [48]. Notably, human embryonic stem cells (ESCs) also displayed a global demethylation upon Dnmt1 deletion [49]. However, in accordance with the special requirement, the DNMT1 and DNMT3A are functionally correlated. For example, in the adult brain, both methyltransferases could carry out cytosine methylation in the promoter and gene body regions, leading to transcription repression [31].

Cytosine Modifications and Distinct Functions of TET1 on Tumorigenesis

http://dx.doi.org/10.5772/intechopen.83709

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While DNMT1 is believed to function mainly for the maintenance of established patterns of DNA methylation in normal living cells, in the diseased cells such as cancer cells, DNMT1 alone is not sufficient to maintain the programmed normal gene hypermethylation. As such, the collaboration of DNMT1 and DNMT3b is indispensable for the maintenance function.

Dnmt3l is believed to function as a stimulator of the Dnmt3A and Dnmt3B, and has related

Sirt1 regulates DNA methylation and differentiation potential of embryonic stem cells by antagonizing Dnmt3l. DNMT2, a tRNA methyltransferase and the most conserved member of the DNMTs methylates tRNAs to protect them from ribonuclease digestion. More importantly, DNMT2 is functionally related to the sperm small RNA (sncRNAs) mediated essentially in writing the "paternal epigenetic signature" to sperm RNA [32]. The mechanism is that the DNMT2-conferred m5C in sncRNAs regulates the secondary structure and biological properties of sncRNAs, suggesting that sperm RNA modifications could serve as one of the

Coordination of the DNA methylation by DNMTs as well as histone modifications contributes

The dynamic DNA methylation/demethylation is tightly regulated during the whole life span. DNA demethylation, the removal of a methyl group, is not just a reverse process of methylation, but rather very complicated metabolic pathways indispensable for reactivation of genes and directly involved in pathogenesis of diseases such as cancers and neurological disorders. Either passive, active, or combination of both, leads to demethylation of DNA. The passive mechanism renders the automatic demethylation in a way that dilution and gradual loss of methylation in the newly synthesized DNA strands during successive replication rounds. In contrast, the active demethylation is believed to be the most important mechanism for active DNA demethylation via 5-mC oxidation catalyzed by the 10-11 translocation proteins (TETs) in alpha-ketoglutarate (a-KG) and Fe(II) dependent manner [22]. In addition to TETs, several other enzymes are acknowledged to be involved in the active mechanisms for demethylation, such as activation-induced cytidine

5-hmC is generated by oxidation of 5-mC by TET, and the 5-hmC faces several fates once it is generated. First, the 5-hmC could be directly converted to regular cytosine through mechanisms

to the regulation of cell death through development, aging, and disease [34, 35].

deaminase (AID) [50], TET [51, 52], and thymine DNA glycosylase (TDG) [53–55].

function with DNMT2 [32, 36–38].

**2.2. Demethylation and demethylases**

carriers for paternally imprinted epigenetic memories [33].

DNA base modifications such as methylation of 5-mC [9–14] and 5-hydroxymethylcytosine (5-hmC) [15–21] have been acknowledged as the best characterized epigenetic markers in mammalian brains [20, 22–24] and ES cells [25–27], essentially regulating chromatin structure and consequently gene expression with the potential mechanisms. This review article mainly focuses on the recent advances in methylation/demethylation modifications of 5-C in mammalian genomes, including methylation/demethylation machineries, methyltransferase complexes (writers) and demethylase complexes (erasers), as well as the distinct functions of TET1 in the regulation of tumorigenesis.
