Epigenetic & Cancer
‘Epigenetic’ is a term used to describe mitotically and meiotically heritable states of gene expression that are not due to changes in DNA sequence1. Epigenetic events are important in all aspects of biology, and research during the past decade has shown that they have a key role in carcinogenesis and tumour progression. Two of the most studied epigenetic phenomena are DNA methylation and histone tail modifications.
DNA is methylated by DNA methyltransferases (DNMTs) at the 5-position (C5) of the cytosine ring, almost exclusively in the context of CpG dinucleotides, which are poorly represented in the genome overall due to spontaneous deamination of 5-methylcytosine into thymine2. Low levels or a lack of DNA methylation in the promoter region is correlated with active gene expression. Approximately 50% of genes are associated with CpG islands in their promoter regions and these CpGs are usually low in methylation and capable of transcriptional activation (CpG islands found elsewhere, such as the body of genes or other non-coding regions of the genome, are sometimes methylated in somatic tissues yet do not block transcription elongation). By contrast, methylation near the transcription start site inhibits gene expression. This is mediated by the recruitment of transcription repressors such as methyl-binding proteins (MBDs), which are part of a large complex that includes histone deacetylases (HDACs)3,4. DNA methylation can also inhibit transcription directly by blocking binding of transcriptional factors such as MYC5.
DNA is wrapped around a core of eight histones to form nucleosomes, the smallest structural unit of chromatin. The basic amino-terminal tails of histones protrude out of the nucleosome and are subject to posttranslational modifications, including acetylation by histone acetyltransferases (HATs) and histone methylation by histone lysine methyltransferases (HMTs). These modifications influence how tightly or loosely the chromatin is compacted, and thereby play a regulatory role in gene expression6. For example, acetyl groups neutralize the positive charges on the basic histone tails, thereby weakening electrostatic interactions between the histones and the
negatively charged phosphate backbone of DNA7.
Most notably, the acetylation of lysine residues on histones H3 and H4 is correlated with active or open chromatin, which allow various transcription factors access to the promoters of target genes. By contrast, deacetylation of lysine residues by HDACs results in chromatin compaction and inactivation of genes.
Unlike histone lysine acetylation, histone lysine methylation can result in either activation or repression, depending on the residue on which it resides. In this way, specific modifications of histone tail residues can be used as ‘markers’ of transcriptionally active or inactive chromatin. For example, histone H3 lysine 4 (H3-K4) methylation is a well-known ‘active’ marker. ‘Inactive’ markers include methylation of H3-K98 and trimethylation of H4-K209. Although only one acetyl group is added to the lysine residue at a time, up to three methyl groups per lysine residue can be present. Interestingly, mono- and dimethylated H3-K9 are found in silent regions located within euchromatic genes, whereas trimethylated H3-K9 is enriched in pericentromeric heterochromatin,
suggesting that the different methylated states mark distinct domains of heterochromatin10. However, methylated H3-K9, along with heterochromatin protein-1γ (HP1γ), has recently been found in the region of active transcription in mammalian chromatin11. The effect of methylation of H3-K9 on transcription activation is not clear and further studies are necessary to define its precise role.
It is widely accepted that histone modification and DNA methylation are intricately interrelated, working together to determine the status of gene expression and to decide cell fate12. A number of DNMT inhibitors and HDAC inhibitors have been shown to have antitumour effects and are being tested in clinical trials.
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