The term “epigenetic” was first coined by Waddington in 1939 to describe diverse reprogramming of the same genetic materials to generate a multicellular organism from a single cell. With new technologies and knowledge, several types of epigenetic modifications—such as DNA methylation, histone modifications, RNA editing, and RNA interference—have been discovered. These modifications are involved in the regulation of gene expression without changing the sequence of DNA. In fact, while genetic codes determine the structure of proteins, epigenetic codes define the time, duration, and amount of protein synthesis in a specific cell or tissue.
Epigenetics has evolved to become the science that explains how the differences in the patterns of gene expression in diverse cells or tissues are executed and inherited. Although heritable, epigenetic programming is influenced by micro and macro environmental factors, and it provides a short-term and generation-specific cellular memory to adapt to variable conditions. It can also be considered as a buffering mechanism to compensate for genetic defects. This dynamic pattern of gene regulation might be a response to internal cues (eg, hormones, neurotransmitters, cellular metabolic states) as well as external cues (eg, neuronal activation, climate changes, seasons, drugs, malnutrition, contaminants). Some epigenetic changes induced by external cues can be transferred to next generation, leading to a disease state.
Many psychiatric disorders, such as bipolar disorder and major depression, are episodic and may spontaneously remit. The episodic nature of these diseases suggests that they are unlikely to be pure genetic diseases, which in general are responsible for the genesis of life-long illness. A multitude of genome-wide association scans of thousands of patients with schizophrenia or bipolar disorder and controls have revealed that while genetic mutations of hundreds of genes appear to be associated with severe mental illness, the effective contribution of each gene is very small (1% to 2%).1 This, along with the fact that the majority of affected individuals do not exhibit any single pattern of genetic mutations, implies that major psychiatric disorders are multifactorial and may involve epigenetic alterations.
In contrast to genetic marks that cannot be restored (at least with the current techniques), epigenetic marks are more amenable to preventive and/or therapeutic modifications using a variety of agents, such as enzymes, hormones, vitamins, nutrients, and drugs (Table 1 and Table 2). The common types of epigenetic modifications are discussed in brief, to provide a rationale for their suitability to design therapeutics.
DNA methylation as a target for epigenetic therapy
DNA methylation, a common epigenetic alteration of the cytosine residue in the context of CpG dinucleotides, has long been detected in mammals. Methylated CpGs are targets for DNA-binding domain proteins such as MBD1, MBD3, MBD4, and MeCP2, which correspond to silencing of gene expression, genomic imprinting, suppression of transposable elements, and X inactivation in females. In the early embryonic stage, DNA methylation marks are erased to generate virtual totipotent cells that then acquire a tissue-specific epigenome that defines the identity and destination of the differentiated cells. Any interference in the process, including the unavailability of the various factors or nutrients (eg, methyl groups, folic acid) may result in an aberrant DNA methylome in the derivative cells.
Hormones or environmental cues can cause demethylation and de novo methylation to alter the inherited pattern of DNA. While DNA methyltransferases convert unmethylated cytosine residues to 5-methylcytosine (5mC), the TET and IDH family proteins convert 5mC to 5-hydroxymethylcytosine (5hmC), a transitional product during demethylation (Table 1). Interestingly, in the brain, a significant fraction of the methylated cytosines are in fact 5hmC and correspond to the induction of gene expression. A dynamic exchange of 5mC and 5hmC may be a key mechanism for functional plasticity of neuronal cells, and an imbalance in the exchange between 5mC and 5hmC may lead to epigenetic dysregulation of many genes underlying psychotic manifestations.
Dr Abdolmaleky is a Visiting Professor/Research Associate in the departments of medicine and genetics and genomics at Boston University School of Medicine, and Research Associate at the Harvard Institute of Psychiatric Epidemiology and Genetics in Boston. Dr Shafa is Scientific Director at Metrowest CNS Research Center, Pharmacogenomics, in Natick, Mass. Dr Tsuang is Distinguished Professor of Psychiatry and Behavioral Genomics Endowed Chair and Director, Center for Behavioral Genomics, department of psychiatry, University of California, San Diego. Dr Tsuang is also Director of the Harvard Institute of Psychiatric Epidemiology and Genetics, Boston. Dr Thiagalingam is an Associate Professor in the departments of medicine, genetics and genomics, and pathology and laboratory medicine at Boston University School of Medicine. The authors report no conflicts of interest concerning the subject matter of this article.
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