Epigenetic control of genes can alter phenotype without altering genotype and the underlying DNA sequence. Epigenetic modifications such as acetylation, methylation, phosphorylation, and ubiquitination, alter the accessibility of DNA to transcription machinery and therefore influence gene expression. Specific epigenetic processes include imprinting, gene silencing, X chromosome inactivation and maternal effects. Epigenetic processes are responsible for many effects of teratogens, and are often associated with the development of cancer. Experimental studies are providing evidence of the influence of epigenetics in disease states, and are establishing a range of novel therapeutic targets
Important epigenetic mechanisms include DNA methylation, histone modification, chromatin remodelling and non-coding RNA-associated gene silencing.
The proteins that carry out these modifications are often described as being either "writers", "readers" or "erasers". Writer enzymes catalyze the addition of chemical groups onto either histone tails or the DNA itself, creating epigenetic marks. Eraser enzymes remove epigenetic marks providing plasticity in epigenetic regulation by facilitating epigenetic reprogramming of genes. DNA demethylation (methylation mark removal) is involved in many important disease mechanisms such as tumor progression. Readers can be enzymes or other proteins which contain structural domains which recognise specific epigenetic marks. See the table below.
In this section we will provide information about DNA methylation and histone modification, including details of some of the enzymes which carry out DNA and histone modifications, implications for disease and pharmacological (drug) interventions at the level of epigenetic control.
DNA methylation
Covalent addition of methyl (CH3) groups is performed by a family of enzymes called DNA methyltransferases (DNMTs), of which DNMT1, -3A and -3B are especially important for the establishment and maintenance of DNA methylation patterns. CH3 methylation marks are added to cytosine residues, and once in place project in to the major groove of DNA and inhibit transcription. Whilst DNMT1 seems to be required for maintaining established DNA methylation patterns, DNMT3A and -3B appear to mediate de novo DNA methylation patterns. In cancer cells DNMT1 and DNMT3B contribute to maintaining gene hypermethylation.
Histone modifications
Histone proteins can be modified in many ways, including lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, and lysine ubiquitination and sumoylation. The unstructured N-termini of histones ('histone tails') are particularly highly modified. Of particular pharmacological relevance are the histone deacetylases (HDACs), which catalyze the hydrolytic removal of acetyl groups from histone lysine residues. HDAC inhibitors have been developed to correct the imbalance in the equilibrium of histone acetylation that is associated with tumorigenesis and cancer progression. Vorinostat was the first HDAC inhibitor to receive regulatory approval (inhibits Class I, II and IV HDACs; approved for cutaneous T-cell lymphoma) and this has been followed by marketing authorisations for romidepsin (Class II HDAC inhibitor; approved to treat cutaneous T-cell lymphoma), belinostat (pan-HDAC inhibitor; approved for relapsed or refractory peripheral T-cell lymphoma) and panobinostat (pan-HDAC inhibitor; approved for multiple myeloma treatment).
A short article and video-cast explaining the proposed molecular mechanism(s) underlying the increased risk of heart attack and stroke associated with COX-2 inhibitor use. Produced by Garret FitzGerald MD FRS from University of Pennsylvania, Perelman School of Medicine.