Pharmacology of epigenetics in brain disorders

Abstract

Epigenetics is a rapidly growing field and holds great promise for a range of human diseases, including brain disorders such as Rett syndrome, anxiety and depressive disorders, schizophrenia, Alzheimer disease and Huntington disease. This review is concerned with the pharmacology of epigenetics to treat disorders of the epigenome whether induced developmentally or manifested/acquired later in life. In particular, we will focus on brain disorders and their treatment by drugs that modify the epigenome. While the use of DNA methyl transferase inhibitors and histone deacetylase inhibitors in in vitro and in vivo models have demonstrated improvements in disease-related deficits, clinical trials in humans have been less promising. We will address recent advances in our understanding of the complexity of the epigenome with its many molecular players, and discuss evidence for a compromised epigenome in the context of an ageing or diseased brain. We will also draw on examples of species differences that may exist between humans and model systems, emphasizing the need for more robust pre-clinical testing. Finally, we will discuss fundamental issues to be considered in study design when targeting the epigenome.

Figure 1

Drugs that can alter epigenetic modifications. DNA methyl transferases (DNMTs) catalyse the transfer of methyl groups from S-adenosyl methionine to cytosine residues within CpG-rich regions of the genome. DNA methylation generally leads to transcriptional silencing. 5-Aza, a DNMT inhibitor can prevent DNA methylation and potentially enable the reactivation of aberrantly silenced genes in the context of disease. Anthracyclines, chromomycin and mithramycin can inhibit transcriptional activators such as Sp1 and Sp2 by competing for their cognate methyl-cytosine binding sites and thus preventing the activation and up-regulation of genes controlled by Sp1/Sp2. The highly regulated interplay between the activity of histone acetyl transferases (which increase acetylation) and histone deacetylases (which decrease acetylation) controls histone acetylation homeostasis. Histone deacetylation closes up the chromatin structure, while histone acetylation generally makes chromatin more accessible for gene activation. Histone deacetylase inhibitors, such as valproic acid, trichostatin A and the butyrates, tilt the balance to increased histone acetylation, and the resulting open chromatin conformation is generally more conducive to increased gene expression.

Figure 2

Dietary components that can alter epigenetics. The enzymes involved in the DNA methylation cycle are dependent on the availability of essential cofactors: folate, and vitamins B12 and B6. In their abundance, DNA methyl transferases (DNMTs) readily transfer methyl groups to cytosine residues; however, in the absence of appropriate cofactors, methionine is converted back to its precursors, homocysteine and S-adenosyl homocysteine. Excess S-adenosyl homocysteine levels inhibit DNMT activity, thus they can reduce/prevent DNA methylation and compromise gene silencing. The cycle can be potentially rescued by supplementation with these essential vitamins, to clear elevated homocysteine levels and restore DNA methylation processes.