Epigenetics 8/1/03. By Richard Twyman Changes to DNA and its associated proteins can alter gene expression without altering the DNA sequence.

DNA does not exist as naked molecules in the cell: it is associated with proteins called histones to form a complex substance known as chromatin.

Chemical modifications to the DNA or the histones alter the structure of the chromatin without changing the nucleotide sequence of the DNA. Such modifications are described as epigenetic.

Changes to the structure of the chromatin have a profound influence on gene expression : if the chromatin is condensed, the factors involved in gene expression cannot get to the DNA, and the genes will be switched off. Conversely, if the chromatin is 'open', the genes can be switched on if required.

While many heritable disorders in humans are caused by DNA sequence changes (mutations) that abolish gene expression, a number of human diseases are caused by inappropriate gene silencing, brought about by epigenetic modifications. Indeed, most cancers involve the epigenetic silencing of genes that normally control cell proliferation. The major forms of epigenetic modification occurring in human tumours are DNA methylation and histone deacetylation.

Epigenetic modifications that abolish gene expression. Top panel – open chromatin is characterised by non-methylated DNA and histones with acetylated tails. This allows the assembly of transcription factors and transcription by RNA polymerase. Middle panel – DNA methyltransferase activity results in the methylation of DNA. This may directly block binding by transcription factors and prevent transcription. It may also recruit methyl-binding domain proteins that have associated histone deacetylases. Bottom panel – DNA methylation and histone deacetylation result in the condensation of chromatin into a compact state that is inaccessible by transcription factors.

DNA methylation is a chemical modification of the DNA molecule itself; it is carried out by an enzyme called DNA methyltransferase. Methylation can directly switch off gene expression by preventing transcription factors binding to promoters.

However, a more general effect is the attraction of methyl-binding domain (MBD) proteins. These are associated with further enzymes called histone deacetylases (HDACs), which function to chemically modify histones and change chromatin structure. Chromatin containing acetylated histones is open and accessible to transcription factors, and the genes are potentially active. Histone deacetylation causes the condensation of chromatin, making it inaccessible to transcription factors and the genes are therefore silenced (see Figure).

Since epigenetic modification plays such an important role in cancer, novel therapeutic strategies are being developed that are based on the reversal of DNA methylation and the inhibition of histone deacetylation. These are being combined with new technologies to rapidly screen the genome for DNA methylation and histone acetylation patterns.

However, diseases can also be caused by inappropriate gene activation. One example is Burkitt's lymphoma, which is caused by the overactivity of a gene called MYC. In this case, the gene is normally found in repressed chromatin and is expressed at a low level. Its function is to promote cell proliferation.

Certain abnormal chromosome rearrangements occurring in lymphocytes move this gene into a region of open and active chromatin, causing the production of large amounts of the protein. The result is the uncontrolled proliferation of lymphocytes, resulting in lymphoma.