Cancer Epigenetics

> In humans, cell differentiation does not involve changes in the base sequence or in the amount of DNA, with few exceptions. Rather, 'epigenetic' mechanisms are employed to establish stable patterns of gene expression. In this case, 'epigenetic' mechanisms are those which establish stably inherited patterns of gene expression in somatic cells without changes in the content or sequence of genomic DNA.

^ Specific epigenetic mechanisms are involved in X-inactivation in female cells and for genomic imprinting, i.e. selective expression of alleles inherited from mother or father. Aberrant genomic imprinting is a cause of certain pediatric tumors, e.g. Wilms tumors. Loss of imprinting is observed in many carcinomas also of older people.

> An important component of epigenetic mechanisms is DNA methylation at cytosine residues in the palindromic CpG dinucleotide sequence. In normal somatic human cells, CpG dinucleotides are mainly methylated in repetitive sequences, in the body of genes and in the regulatory regions of non-expressed genes. In contrast, relatively CpG-rich sequences overlapping the transcriptional start site of many human genes, called 'CpG-islands', are usually devoid of methylation.

> In many human tumors, some CpG-islands become aberrantly methylated. This 'hypermethylation' as a rule is associated with silencing of the hypermethylated gene. In spite of such increases in methylation at specific sites, the overall methylcytosine content is decreased in many tumor cells, owing to partial demethylation of repetitive sequences and gene coding regions. This phenomenon is designated 'global hypomethylation'. It may be related to chromosomal instability. Both changes are relatively straightforwardly detected and monitored, and can be used for tumor diagnostics.

> DNA methylation is one of several interacting mechanisms that down-regulate gene expression in an increasingly stable fashion. The most dynamical of these mechanisms is deacetylation of histones in the nucleosomes of gene regulatory regions. Acetylation is enhanced by transcriptional activators binding to DNA and by co-activators with histone acetylase (HAT) activity. Conversely, deacetylation is catalyzed by histone deacetylases (HDACs) recruited by repressors or co-repressors. Methylation of histones at specific sites, prominently at the K9 of H3, by histone methyltransferases (HMTs) is a further step towards inactivation, while methylation at other sites, e.g. K4 of H3 stabilizes gene activation. Modification at K9 attracts repressor proteins, e.g. HP1, but also DNA methyltransferases (DNMTs), which 'lock in' gene silencing. DNA methylation directly inhibits the binding of some transcriptional activators and promotes the binding of repressory protein complexes which recognize methylcytosine via MBD proteins. DNMTs also interact with HDACs and HMTs, thereby reinforcing silencing. Gene activation as well as gene inactivation employ chromatin remodeling complexes which mutually interact with activators and repressors.

> Aberrant gene silencing by epigenetic mechanisms in tumor cells is often, but not always accompanied by DNA hypermethylation. The underlying rules are not understood. A variety of HATs, HDACs, HMTs, and chromatin remodeling factors are implicated as oncogenes or tumor suppressors in human cancers.

> Activated gene states are also propagated by epigenetic mechanisms, including specific chromatin modifications. While epigenetic mechanisms leading to inappropriate gene over-expression in human cancers are overall less well understood than those leading to gene silencing, it is clear that epigenetic mechanism contribute to the inappropriate expression of oncogenic proteins.

^ The concept of 'epigenetics' can be extended to include phenomena beyond the nucleus and even beyond a single cell. It is likely that such mechanisms contribute to the establishment of stably inherited patterns of gene expression in normal tissues and in tumors. They could encompass autoregulatory loops in transcription factor networks or growth factor signal transducing pathways acting within one cell, but also stable interaction loops between different cell types, particularly mesenchymal and epithelial cells or stromal and carcinoma cells.

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