Non-coding RNAs, such as microRNAs (miRNAs), which are 20 to 25 bases in length, are another important feature of epigenetic regulation. In general, miRNAs bind to target messenger RNAs (mRNAs) and inhibit the translation or degrade mRNAs and prevent protein synthesis. Remarkably, each gene can be targeted by multiple miRNAs and each miRNA (approximately 1000 known) may target hundreds of mRNAs. In addition to intracellular regulation of gene expression, miRNAs can affect the expression of various genes (eg, metabolic genes) far from the locations from which they were generated in the form of circulating miRNAs.
A number of studies have uncovered close to 2 dozen miRNAs affected in psychiatric disorders (Table 3). A microarray analysis showed decreased expression of 16 miRNAs in the frontal lobe of postmortem brains in patients with schizophrenia and schizoaffective disorder.14 The assay included miR-24, miR-26b, miR-30e, and miR-92, and results were confirmed by quantitative real-time polymerase chain reaction analysis.
Increased miRNA biogenesis in the superior temporal gyrus and dorsolateral prefrontal cortex and overexpression of miR-15a, miR-15b, miR-195, and miR-107 were also found in patients with schizophrenia. These miRNAs have the capacity to regulate the expression of target genes, including ATXN2, BDNF, CHRM1, DRD1, GABR1, GRIN1, GRM7, HTR4, NRG1, and RELN, which are known to be affected in schizophrenia.15 Overexpression of miR-181b was found to be associated with reduced expression of VSNL1 (which regulates the activity of adenylyl cyclase) and GRIA2 (glutamate receptor, ionotropic, AMPA 2) in the gray matter of the temporal cortex in postmortem brain samples of patients with schizophrenia. Subsequent studies verified that the expression of VSNL1 and GRIA2 is suppressed by synthetic miR-181b in cell culture experiments.16
Other targets of miR-181b are genes coding receptors for GABA (GABRA1), glutamate (GRID, GRIK2, GRM5, and GRM7), or serotonin (HTR1B and HTR2C), which contribute to the pathogenesis of mental diseases. GRID1 and miR-346, which are localized to the intron 2 of GRID1, exhibited reduced expression in postmortem brain samples of patients with schizophrenia.17
Recent findings suggest an increased expression of exosomal miR-497 and miR-29c in the postmortem prefrontal cortices of patients with schizophrenia and bipolar disorder, respectively, and a decrease in circulating miR-134 in the plasma of drug-free patients in the manic phase of bipolar disorder.18,19
Collectively, the progress made in miRNA studies not only indicates that these non-coding regulatory RNAs may contribute to the pathogenesis of psychiatric diseases and mediate the effects of mood stabilizers but also suggests the potential use of circulating miRNAs as diagnostic biomarkers and the use of synthetic miRNAs (that mimic the activity of circulating or brain specific miRNAs) as therapeutic tools.
Conclusion and perspectives
The major challenges for epigenetic therapies are target specificity of the drugs—an issue that is also true for most of the currently used drugs in medicine, especially in psychiatry. Recent discoveries on the use of zinc finger proteins and other tools such as TALEN (transcription activator-like effector nucleases) that recognize specific DNA sequences have paved the way for the recruitment of regulatory proteins, enzymes, and drugs to gene promoters for site-specific epigenetic modifications.20 However, the mechanisms that deliver the modifiers to specific neuronal nuclei or pathways are still to be identified.
Concurrent activation of a desired pathway using transcranial magnetic stimulation (TMS) or other tools may help to deliver the specific epigenetic modifiers to the activated pathways or neuronal nuclei by the mediation of glucose or other molecules that are utilized at a higher rate by the activated cells. Given that electroconvulsive therapy–induced neuronal activity is a powerful epigenetic modifier in the adult brain and that the abnormal epigenomic brain map for psychiatric disorders is under development, epigenetic modifications of specific brain regions using noninvasive methods such as TMS may be among the epigenetic therapies coming over the horizon.21
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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