Although genetics have played a dominant role in cancer, in recent years the importance of epigenetic regulation of chromatin states through specific modifications to DNA or histones has become widely recognized [62, 284]. Thetermepigeneticisderived from theGreek forupon, epi,and canbeviewed as a secondary level of cellular information, in addition to the genomic DNA sequence, that maybe passed on during cell division. There are three conduits through which epigenetic information has thus far been shown to be conveyed: via genomic DNA methylation, histone modification and silencing of genes on parent-of-origin-specific alleles by genomic imprinting. Many of the enzymes responsible for the establishment of specific epigenetic modifications have been identified to date and some have been shown to directly associate with leukaemogenic fusion proteins, such as t(15;17)-associated PML-RARa in APL . An important characteristic of these epigenetic modifications is their potential reversibility, and molecular therapies that target the underlying processes responsible for their deposition have been the focus of intense research .
Epigenetic modification of genomic DNA is characterized by methylation of cytosine and is important for gene repression in mammals and plants, although it does not occur in a number of eukaryotes including Saccharomyces cerevisiae and Caenorhabditis elegans . In animal genomes, the cytosine residues of cytosine-guanine pairs (CpG) are often methylated , a reaction catalysed by members of the DNA methyltransferase (DNMT) family. Methylation can occur as part of a maintenance mechanism during DNA replication and repair, carried out by Dnmt1, as well as through de novo methylation by Dnmt3a or Dnmt3b . Between 60% and 80% of all CpG din-ucleotides are methylated in animal genomes and approximately 60% of genes have promoters containing dense regions of CpGs, called CpG islands, which in contrast to other CpG dinucleotides, are often unmethylated [5,16]. In normal cells, the majority of CpG methylation occurs in heterochromatic DNA and is generally considered to facilitate static long-term gene silencing, and also to confer genome stability through repression of transposons and repetitive DNA elements . Where methylation of CpG islands does occur, it leads to gene repression as evidenced by the silencing of tumour-suppressor genes during cancer progression, a process accompanied by genomic global hypomethyla-tion . Although the extent to which aberrant promoter hypermethylation plays a role in cancer initiation remains unresolved , there is some evidence for a "CpG island methylator phenotype" in some cell types .
The other central tenet of the epigenetic control of gene expression is the histone code [248,261], which provides a means whereby input signals can be interpreted by a cell and translated into a heritable pattern of gene expression that defines a particular cellular output state or states (for a recent review see Margueron et al. ). Although it is clear that information encoded by histones is transmissible to daughter cells, the underlying mechanisms by which this occurs are not yet well understood . The histone code itself is a combinatorial array of post-translational modifications (acetylation, phosphorylation, methylation, ubiquitination, sumoylation, for example) of N-terminal tails of core histone and to a lesser degree their globular domains. Probably the most studied component of this code, both in terms of the residues affected and the consequences for transcriptional activity, is histone acetylation. Multiple lysines on each of the core histones can be dynamically modified by reversible acetylation . The acetylation reaction is catalysed by histone acetyltransferases, which modify the e-amino group of histone lysine residues in an acetyl-CoA dependent reaction, whilst removal of acetyl group is catalysedbyhistone deacetylases. Hyperacetylatedhistones are stably associated with transcriptionally active domains and more accessible chro-matin structure, whereas hypo-acetylated histones are enriched in regions that are transcriptionally silent . Over the past few years, the complexity of cross-talk between different histone modifications, which can involve both same and different histones in the nucleosome, as well as between histones and DNA methylation, has begun to emerge . For example, in mammalian cells, various degrees of histone H3 Lys9 methylation and histone hypoacety-lation are usually associated with methylated DNA, heterochromatin and gene silencing. Histone hyperacetylation and methylation of H3 Lys4, on the other hand, are associated with unmethylated DNA, euchromatin and gene expression [139,164]. Various DNA or histone markers that constitute active or inactive chromatin states, together with details of the cross-talk between them and the enzymes responsible for their deposition are shown in Fig. 1.
Pranotef hypomelhylalion demelhylase? Pramoler hypennetfiylaliafi H3/H4 Lysina+
Fig. 1 Markers of active and inactive chromatin states. Active euchromatin: various biochemical markers found on the core histones are boxed in green. Reciprocal arrows indicate where a particular marker can influence the acquisition of another. Single arrows reflect a situation where the deposition of a marker enhances or has been demonstrated to be necessary for the acquisition of another. The reciprocal arrows in between promoter hypomethylation and euchromatic histone markers refer to the reinforcement of the active state that occurs as a result of HATs, for example, gaining access to 'open' chromatin and depositing acetyl lysine markers that, in turn, provide anchorage sites for coactivators and components of the transcription initiation complex. TA denotes a transcriptional activator. Silent heterochromatin: various proteins associated with transcriptionally inactive chromatin are indicated. Lysine+ refers to positively charged, unacetylated histone H3 or H4. Recent evidence suggests that each epigenetic modification (histone acetylation, DNA methylation, histone methylation) can influence the acquisition of the other two (indicated by reciprocal arrows). Initiation of the heterochromatic state may occur through sequence-specific DNA binding proteins (TR) that promote either histone methylation or histone deacetylation, and subsequent recruitment of specific co-repressors and the general silencing machinery. DNMTs may also be recruited in this manner. Gene silencing and formation of heterochromatin may proceed through changing the balance of dynamic processes, e.g. histone acetylation/deacetylation, or deposition of long-term markers such as DNA or histone methylation. Maintenance of the repressive heterochromatic state is achieved through binding of proteins to specific histone modules (for example HPla for methylated H3 Lys9); or to methylated CpG dinucleotide sequences [methylDNA binding proteins (MBD)]. The enzymes responsible for the transition between the active and silent chromatin states are indicated. DNA demethylase activity is represented by a dashed line because, although an active DNA demethylase has been postulated , its existence remains to be established
Although many aspects of the mechanisms that are responsible for establishing pathological epigenetic changes remain to be elucidated, two nonexclusive models have emerged over the past years. In a stochastic model, overexpression of a given component of the machinery responsible for writ ing epigenetic code may increase probability of its mistargeting and causing deregulated expression of a gene important for tumourigenesis (tumour suppressor or oncogene) . This is consistent with experimental findings indicating over-expression of some histone and DNA-modifying enzymes in cancer [32,61,133, 244]. In the other scenario, as mentioned above, chromatin-modifying complexes are inappropriately targeted to regulatory regions of specific genes by AML-associated fusion oncoproteins such as PML-retinoic acid receptor a (RARa) or PLZF-RARa [54,160,297, 298].
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