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Schizophrenia is associated with an increase in cortical microRNA biogenesis.

Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ - Mol. Psychiatry (2009)

Bottom Line: MicroRNA expression profiling and quantitative reverse transcription-PCR analysis of the superior temporal gyrus and the dorsolateral prefrontal cortex revealed a significant schizophrenia-associated increase in global microRNA expression.This change was associated with an elevation of primary microRNA processing and corresponded with an increase in the microprocessor component DGCR8.The biological implications for this extensive increase in gene silencing are profound, and were exemplified by members of the miR-15 family and other related microRNA, which were significantly upregulated in both brain regions.

View Article: PubMed Central - PubMed

Affiliation: Schizophrenia Research Institute, Sydney, NSW, Australia.

ABSTRACT
MicroRNA expression profiling and quantitative reverse transcription-PCR analysis of the superior temporal gyrus and the dorsolateral prefrontal cortex revealed a significant schizophrenia-associated increase in global microRNA expression. This change was associated with an elevation of primary microRNA processing and corresponded with an increase in the microprocessor component DGCR8. The biological implications for this extensive increase in gene silencing are profound, and were exemplified by members of the miR-15 family and other related microRNA, which were significantly upregulated in both brain regions. This functionally convergent influence is overrepresented in pathways involved in synaptic plasticity and includes many genes and pathways associated with schizophrenia, some of which were substantiated in vitro by reporter gene assay. Given the magnitude of microRNA changes and their wide sphere of influence, this phenomenon could represent an important dimension in the pathogenesis of schizophrenia.

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Schizophrenia-associated miRNA expression in the dorsolateral prefrontal cortex (DLPFC). (a) miRNA expression in the DLPFC in schizophrenia was characterized by the global upregulation illustrated in this scatter plot (see Figure 1a for description), with the majority of individual miRNAs showing a ratio >1.0. (b) Increased miRNA expression in the DLPFC was validated using quantitative real-time reverse transcription-PCR (Q-PCR) (n=15 matched pairs). Level of expression for controls was set at 1. (c) Further Q-PCR expression analysis indicated that 11 miRNAs with altered expression showed an upregulation in both the superior temporal gyrus and DLPFC. Bars indicate mean fold change+s.e.m. *P<0.05; **P<0.01; ***P<0.001. (d) Q-PCR expression data were subjected to hierarchical clustering and heat map, shown as described in Figure 1d.
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fig2: Schizophrenia-associated miRNA expression in the dorsolateral prefrontal cortex (DLPFC). (a) miRNA expression in the DLPFC in schizophrenia was characterized by the global upregulation illustrated in this scatter plot (see Figure 1a for description), with the majority of individual miRNAs showing a ratio >1.0. (b) Increased miRNA expression in the DLPFC was validated using quantitative real-time reverse transcription-PCR (Q-PCR) (n=15 matched pairs). Level of expression for controls was set at 1. (c) Further Q-PCR expression analysis indicated that 11 miRNAs with altered expression showed an upregulation in both the superior temporal gyrus and DLPFC. Bars indicate mean fold change+s.e.m. *P<0.05; **P<0.01; ***P<0.001. (d) Q-PCR expression data were subjected to hierarchical clustering and heat map, shown as described in Figure 1d.

Mentions: In view of the possibility that these changes in miRNA expression were merely STG-related phenomena, we initiated a similar investigation of the DLPFC (BA9), a region most frequently identified in the neuropathology of schizophrenia. Total RNA from post-mortem gray matter from a cohort of 15 cases with a history of schizophrenia and 15 matched controls with no record of psychiatric illness was extracted and subjected to microarray analysis as described for the STG. The miRNA expression profile in this tissue was similar to that in the STG, with 274 expressed miRNAs (compared with 280 in the STG). Importantly, the DLPFC showed a schizophrenia-associated global increase in miRNA expression that was broadly consistent with the observations in the STG (Figure 2a). According to SAM analysis, 26 (9.5%) of the miRNAs expressed in the DLPFC were significantly upregulated, such as miR-181b, miR-16 and miR-20a, which were also increased in the STG.


Schizophrenia is associated with an increase in cortical microRNA biogenesis.

Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ - Mol. Psychiatry (2009)

Schizophrenia-associated miRNA expression in the dorsolateral prefrontal cortex (DLPFC). (a) miRNA expression in the DLPFC in schizophrenia was characterized by the global upregulation illustrated in this scatter plot (see Figure 1a for description), with the majority of individual miRNAs showing a ratio >1.0. (b) Increased miRNA expression in the DLPFC was validated using quantitative real-time reverse transcription-PCR (Q-PCR) (n=15 matched pairs). Level of expression for controls was set at 1. (c) Further Q-PCR expression analysis indicated that 11 miRNAs with altered expression showed an upregulation in both the superior temporal gyrus and DLPFC. Bars indicate mean fold change+s.e.m. *P<0.05; **P<0.01; ***P<0.001. (d) Q-PCR expression data were subjected to hierarchical clustering and heat map, shown as described in Figure 1d.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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fig2: Schizophrenia-associated miRNA expression in the dorsolateral prefrontal cortex (DLPFC). (a) miRNA expression in the DLPFC in schizophrenia was characterized by the global upregulation illustrated in this scatter plot (see Figure 1a for description), with the majority of individual miRNAs showing a ratio >1.0. (b) Increased miRNA expression in the DLPFC was validated using quantitative real-time reverse transcription-PCR (Q-PCR) (n=15 matched pairs). Level of expression for controls was set at 1. (c) Further Q-PCR expression analysis indicated that 11 miRNAs with altered expression showed an upregulation in both the superior temporal gyrus and DLPFC. Bars indicate mean fold change+s.e.m. *P<0.05; **P<0.01; ***P<0.001. (d) Q-PCR expression data were subjected to hierarchical clustering and heat map, shown as described in Figure 1d.
Mentions: In view of the possibility that these changes in miRNA expression were merely STG-related phenomena, we initiated a similar investigation of the DLPFC (BA9), a region most frequently identified in the neuropathology of schizophrenia. Total RNA from post-mortem gray matter from a cohort of 15 cases with a history of schizophrenia and 15 matched controls with no record of psychiatric illness was extracted and subjected to microarray analysis as described for the STG. The miRNA expression profile in this tissue was similar to that in the STG, with 274 expressed miRNAs (compared with 280 in the STG). Importantly, the DLPFC showed a schizophrenia-associated global increase in miRNA expression that was broadly consistent with the observations in the STG (Figure 2a). According to SAM analysis, 26 (9.5%) of the miRNAs expressed in the DLPFC were significantly upregulated, such as miR-181b, miR-16 and miR-20a, which were also increased in the STG.

Bottom Line: MicroRNA expression profiling and quantitative reverse transcription-PCR analysis of the superior temporal gyrus and the dorsolateral prefrontal cortex revealed a significant schizophrenia-associated increase in global microRNA expression.This change was associated with an elevation of primary microRNA processing and corresponded with an increase in the microprocessor component DGCR8.The biological implications for this extensive increase in gene silencing are profound, and were exemplified by members of the miR-15 family and other related microRNA, which were significantly upregulated in both brain regions.

View Article: PubMed Central - PubMed

Affiliation: Schizophrenia Research Institute, Sydney, NSW, Australia.

ABSTRACT
MicroRNA expression profiling and quantitative reverse transcription-PCR analysis of the superior temporal gyrus and the dorsolateral prefrontal cortex revealed a significant schizophrenia-associated increase in global microRNA expression. This change was associated with an elevation of primary microRNA processing and corresponded with an increase in the microprocessor component DGCR8. The biological implications for this extensive increase in gene silencing are profound, and were exemplified by members of the miR-15 family and other related microRNA, which were significantly upregulated in both brain regions. This functionally convergent influence is overrepresented in pathways involved in synaptic plasticity and includes many genes and pathways associated with schizophrenia, some of which were substantiated in vitro by reporter gene assay. Given the magnitude of microRNA changes and their wide sphere of influence, this phenomenon could represent an important dimension in the pathogenesis of schizophrenia.

Show MeSH
Related in: MedlinePlus