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Psychiatric Epigenetics: A Key to the Molecular Basis of and Therapy for Psychiatric Disorders: Page 2 of 3

Psychiatric Epigenetics: A Key to the Molecular Basis of and Therapy for Psychiatric Disorders: Page 2 of 3

Table 1: Some important enzymes involved in epigenetic modificationsTable 1: Some important enzymes involved in epigenetic modifications
Table 2: Examples of known epigenetic modifiers with therapeutic implications orTable 2: Examples of known epigenetic modifiers with therapeutic impli...
Table 3: Epigenetic aberrations reported in psychiatric diseaseTable 3: Epigenetic aberrations reported in psychiatric disease

The results of a postmortem study of the human brain showed that 5hmC levels at the GAD67 promoter in the inferior parietal lobule of patients with schizophrenia and bipolar disorder were increased compared with levels in controls.2 The increased levels of 5hmC in GAD67 are associated with a greater than 2-fold increase in TET1 expression. An increase in GADD45b expression (which is involved in DNA demethylation) was also seen in psychotic patients.3

A recent whole genome DNA methylation microarray analysis found that methylation values at 2868 CpG sites in DNA extracted from the saliva of 96 maltreated children were significantly different from those of controls.4 Another genome-wide DNA methylation analysis of the peripheral blood DNA in humans uncovered disease-associated aberrant DNA methylation of numerous CpGs in twins affected by schizophrenia and bipolar disorder versus discordant twins, among whom hypomethylation of the ST6GALNAC1 gene promoter was observed in postmortem brain tissue from those with psychosis.5

Data from the studies reviewed elsewhere6 and summarized in Table 3 show aberrant promoter DNA methylation of specific genes, including RELN, SOX10, WDR18, MB-COMT, and HTR2A, in postmortem brain samples of patients who had major psychiatric disorders.7 Recent whole genome DNA methylation studies of postmortem brain samples (H. M. Abdolmaleky and S. Thiagalingam, unpublished data, 2013) and of peripheral leukocytes identified specific DNA methylation changes8,9; and global DNA hypomethylation became attenuated with haloperidol treatment.9 Melas and colleagues9 found hypermethylation of soluble catechol-O-methyltransferase (s-COMT) in schizophrenia; another study suggested that s-COMT promoter DNA methylation is influenced by the 158Val/Met polymorphism as well as by physical activity.10 These observations support evidence that in addition to drugs and genetic polymorphisms, external cues may also modify epigenetic codes.

While more studies are required to identify the major affected pathways and genes, the existing data have influenced the use of drugs with epigenetic effects in treating patients with psychiatric disorders. At this time, the most remarkable drug seems to be sodium valproate, an “epigenetic softener” that indirectly decreases promoter DNA methylation through the inhibition of histone deacetylase (HDAC) enzymes. However, in the case of DNA hypomethylation (eg, in malnutrition, MDD, Alzheimer disease), the use of folic acid, vitamin B12, and L-methionine has been considered.6

Histone modifications and current therapeutics

Histone modifications are major epigenetic mechanisms closely tied with DNA methylation and frequently considered as a therapeutic target for various diseases. An octamer of positively charged histone core proteins (H2A, H2B, H3, H4) with the H1 linker histone (which are wrapped by 147 base pairs of DNA strands with a negative electric charge) constitutes the nucleosome (the building unit of chromatin assembled in chromosomes). Histone tails are subjected to various modifications, such as methylation, acetylation, and phosphorylation, that determine the transcriptionally active status of the chromatin as well as the accessibility to transcription factors. Several enzymes are involved in diverse types of histone modifications and, thus, induction or suppression of gene expression (Table 1). For instance, histone methyltransferases add and histone demethylases remove methyl groups of histone tails that, in turn, can, depending on the sequence context of the amino-acid residue, switch on or switch off gene expression. The target amino acids of histone tails can be mono-methylated, bi-methylated, or tri-methylated, making their functional status more complex (Table 1).

Activation or suppression of some of the enzymes that mediate epigenetic modifications have been used to treat many diseases, including major psychiatric disorders (Table 2). Valproate is an HDAC inhibitor, and it increases the level of histone acetylation. Lithium also increases the levels of histone H3 acetylation and phosphoacetylation in the central nucleus of the amygdala, which is associated with the induction of c-Fos.11 Haloperidol, clozapine, and benzamides have similar effects. Imipramine, amitriptyline, fluoxetine, escitalopram, tranylcypromine, and opioids are also epigenetic modifiers (see Table 2 for more details). Although the expression of HDAC1, HDAC2, and HDAC5 is higher with lurasidone than with valproate treatment, concomitant use of valproate led to higher brain-derived neurotrophic factor (BDNF) expression in the ventral hippocampus compared with either drug alone.12

RNA editing

RNA editing that includes substitution, deletion, or insertion of ribonucleotides corresponding to a coding DNA sequence can generate multiple variants of a single protein in diverse tissues, particularly in the brain as the result of neuronal activity. Multiple forms of serotonin, glutamate, and γ-aminobutyric acid (GABA) receptors with different functional and pharmacological properties that originate from RNA editing have been recognized in humans. Hence, some drugs that in-hibit or stimulate these targets in other tissues may fail to act in the human brain.13 In fact, the diversity of RNA editing in the human brain may underlie region-specific effects of modern antipsychotic drugs that are known for fewer adverse effects. A better understanding of this mechanism of epigenetic modification could provide opportunities for designing better drugs to target the exact variants of specific receptors, channels, or enzymes in particular areas of the brain in affected individuals.


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