|Mol. Psychiatry 2012 Jul 17: 827-40
|Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells.
|MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level and are important for coordinating nervous system development and neuronal function in the mature brain. We have recently identified schizophrenia-associated alteration of cortical miRNA biogenesis and expression in post-mortem brain tissue with implications for the dysregulation of schizophrenia candidate genes. Although these changes were observed in the central nervous system, it is plausible that schizophrenia-associated miRNA expression signatures may also be detected in non-neural tissue. To explore this possibility, we investigated the miRNA expression profile of peripheral blood mononuclear cells (PBMCs) from 112 patients with schizophrenia and 76 non-psychiatric controls. miRNA expression analysis of total RNA conducted using commercial miRNA arrays revealed that 33 miRNAs were significantly downregulated after correction for multiple testing with a false discovery rate (FDR) of 0%, which increased to 83 when we considered miRNA with an FDR<5%. Seven miRNAs altered in microarray analysis of schizophrenia were also confirmed to be downregulated by quantitative real-time reverse transcription-polymerase chain reaction. A large subgroup consisting of 17 downregulated miRNAs is transcribed from a single imprinted locus at the maternally expressed DLK1-DIO3 region on chromosome 14q32. This pattern of differentially expressed miRNA in PBMCs may be indicative of significant underlying genetic or epigenetic alteration associated with schizophrenia.
|Transl Psychiatry 2014 -1 4: e452
|Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure.
|A significant feature of the cortical neuropathology of schizophrenia is a disturbance in the biogenesis of short non-coding microRNA (miRNA) that regulate translation and stability of mRNA. While the biological origin of this phenomenon has not been defined, it is plausible that it relates to major environmental risk factors associated with the disorder such as exposure to maternal immune activation (MIA) and adolescent cannabis use. To explore this hypothesis, we administered the viral mimic poly I:C to pregnant rats and further exposed some of their maturing offsprings to daily injections of the synthetic cannabinoid HU210 for 14 days starting on postnatal day 35. Whole-genome miRNA expression analysis was then performed on the left and right hemispheres of the entorhinal cortex (EC), a region strongly associated with schizophrenia. Animals exposed to either treatment alone or in combination exhibited significant differences in the expression of miRNA in the left hemisphere, whereas the right hemisphere was less responsive. Hemisphere-associated differences in miRNA expression were greatest in the combined treatment and highly over-represented in a single imprinted locus on chromosome 6q32. This observation was significant as the syntenic 14q32 locus in humans encodes a large proportion of miRNAs differentially expressed in peripheral blood lymphocytes from patients with schizophrenia, suggesting that interaction of early and late environmental insults may affect miRNA expression, in a manner that is relevant to schizophrenia.