Making Sense of Epigenetics

Abstract

The gene-environment interactions that underlie development and progression of psychiatric illness are poorly understood. Despite a century of progress, genetic approaches have failed to identify new treatment modalities, perhaps because of the heterogeneity of the disorders and lack of understanding of mechanisms. Recent exploration into epigenetic mechanisms in health and disease has uncovered changes in DNA methylation and chromatin structure that may contribute to psychiatric disorders. Epigenetic changes suggest a variety of new therapeutic options due to their reversible chemistry. However, distinguishing causal links between epigenetic changes and disease from changes consequent to life experience has remained problematic. Here we define epigenetics and explore aspects of epigenetics relevant to causes and mechanisms of psychiatric disease, and speculate on future directions.

Keywords: DNA methylation; chromatin; epigenetics; neuropsychiatric disorders.

Figure 1.

Epigenetic and genetic alterations of DNA. Epigenetic changes, including methylation and hydroxymethylation of cytosines and other nucleotides, chromatin condensation and opening, and the shortening and lengthening of telomeres, are reversible and thus provide a capacity to rapidly adapt to changes in the environment (lightning bolt). Genetic changes, including DNA substitutions, insertion/deletions (not shown), recombination, and viral integration/transposition, are primarily irreversible. For example, it is rare that a second point mutation exactly reverses a mutation or that a second recombination event occurs at precisely the same location as a previous recombination event. The magnitude of reversibility is shown by the length of the blue arrow.

Figure 2.

DNA epigenetic modifications and their editors. The 2 best-known DNA modifications are methylation (5m) and hydroxymethylation (5hm). Other nucleotides can be modified, but DNA methylation preferentially occurs on cytosine nucleotides adjacent to guanine nucleotides, a modification catalyzed by DNA methyltransferases (DNMTs). DNA methylation generally silences transcription whereas hydroxymethylation generally activates transcription, although exceptions are now widely known, and seem to be related to the genomic feature (e.g., promoter, intragenic region, 3’ UTR) in which the epigenetic modification is located.

Figure 3.

The histone code and its modifiers. The basic functional unit of chromatin is the nucleosome, which is composed of 147bp of DNA wrapped tightly around an octamer of histone proteins (H2A, H2B, H3, and H4). Histone tails project from nucleosomes and are subject to posttranslational modifications, including methylation (Me), acetylation (Ac), phosphorylation (P), phosphoacetylation (p-Ac), ubiquitination (Ub), and ADP-ribosylation (ADP-R), in different combinations. Local combinations of differentially modified histone proteins form histone codes. Histone codes enhance or inhibit transcription by recruiting enzymes that catalyze the opening or condensing of chromatin, thus making the DNA more or less accessible to transcription factors and additional regulatory factors that modify transcription. The histone code is edited by an ensemble of enzymatic writers, erasers, and readers. Writers add covalent modifications. Erasers catalyze removal of modifications. Readers recognize and bind specific motifs.