Characterising the Transcriptional and Translational Impact of the Schizophrenia-associated miR-1271-5p in Neuronal Cells
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ABSTRACT:
PROVIDER: PRJNA625926 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11560808.fastq.gz | Fastqsanger.gz | |||
| SRR11560809.fastq.gz | Fastqsanger.gz | |||
| SRR11560810.fastq.gz | Fastqsanger.gz | |||
| SRR11560811.fastq.gz | Fastqsanger.gz | |||
| SRR11560812.fastq.gz | Fastqsanger.gz |
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Project description:Here, we investigated the transcriptome-wide impact of schizophrenia-associated miR-1271-5p in response to bidirectional modulation. Alteration of miR-1271-5p induced considerable changes to mRNA abundance and translation which spanned a diverse range of cellular functions, including directly targeted genes strongly associated with cytoskeletal dynamics and cellular junctions. Mechanistic analyses additionally revealed that upregulation of miR-1271-5p predominantly repressed mRNAs through destabilisation, wherein 3´UTR and CDS binding sites exhibited similar efficacy. Knockdown, however, produced no discernible trend in target gene expression and strikingly resulted in increased expression of the highly conserved miR-96-5p which shares an identical seed region with miR-1271-5p, suggesting the presence of feedback mechanisms which sense disruptions to miRNA levels. These findings indicate that while bidirectional regulation of miR-1271-5p results in substantial remodelling of the neuronal transcriptome, these effects are not inverse in nature. In addition, we provide further support for the idea that destabilisation of mRNA is the predominant mechanism by which miRNAs regulate complementary mRNAs.
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Project description:MicroRNA (miRNA) coordinate complex gene expression networks in cells that are vital to support highly specialised morphology and cytoarchitecture. Neurons express a rich array of miRNA, including many that are specific or enriched, which have important functions in this context and implications for neurological conditions. While the neurological function of a number of brain-derived miRNAs have been examined thoroughly, the mechanistic basis of many remain obscure. In this case, we investigated the transcriptome-wide impact of schizophrenia-associated miR-1271-5p in response to bidirectional modulation. Alteration of miR-1271-5p induced considerable changes to mRNA abundance and translation, which spanned a diverse range of cellular functions, including directly targeted genes strongly associated with cytoskeletal dynamics and cellular junctions. Mechanistic analyses additionally revealed that upregulation of miR-1271-5p predominantly repressed mRNAs through destabilisation, wherein 3'UTR and coding sequence binding sites exhibited similar efficacy. Knockdown, however, produced no discernible trend in target gene expression and strikingly resulted in increased expression of the highly conserved miR-96-5p, which shares an identical seed region with miR-1271-5p, suggesting the presence of feedback mechanisms that sense disruptions to miRNA levels. These findings indicate that, while bidirectional regulation of miR-1271-5p results in substantial remodeling of the neuronal transcriptome, these effects are not inverse in nature. In addition, we provide further support for the idea that destabilisation of mRNA is the predominant mechanism by which miRNAs regulate complementary mRNAs.
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Project description:Recent evidence supports a role of microRNAs in cancer and psychiatric disorders such as schizophrenia and bipolar disorder, through their regulatory role on the expression of multiple genes. The rather rare co-morbidity of cancer and schizophrenia is an old hypothesis which needs further research on microRNAs as molecules that might exert their oncosuppressive or oncogenic activity in the context of their role in psychiatric disorders The expression pattern of a variety of different microRNAs was investigated in patients (N=6) suffering from schizophrenia termed control, patients with a solid tumor (N=10) and patients with both schizophrenia and tumor (N=8). miRNA profiling was performed on whole blood samples using the miRCURY LNA™ microRNA Array technology (6th & 7th generation). Significant down-regulation of the let-7p-5p, miR-98-5p and of miR-183-5p in the study groups (tumor alone and tumor and schizophrenia) was observed (p<0.05). let-7, miR-98 and miR-183 may play an important oncosuppressive role through their regulatory impact in gene expression irrespective of the presence of schizophrenia
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Project description:While the pathophysiology of schizophrenia has been extensively investigated using homogenized postmortem brain samples, few studies have examined changes in brain samples with techniques that may attribute perturbations to specific cell types. To fill this gap, we performed microarray assays on mRNA isolated from anterior cingulate cortex (ACC) superficial and deep pyramidal neurons from 12 schizophrenia and 12 control subjects using laser capture microdissection. Among all the annotated genes, we identified 134 significantly increased and 130 decreased genes in superficial pyramidal neurons, while 93 significantly increased and 101 decreased genes were found in deep pyramidal neurons, in schizophrenia compared to control subjects. In these differentially expressed genes, we detected lamina-specific changes of 55 and 31 genes in superficial and deep neurons in schizophrenia, respectively. Gene set enrichment analysis (GSEA) was applied to the entire pre-ranked differential expression gene lists to gain a complete pathway analysis throughout all annotated genes. Our analysis revealed over-represented groups of gene sets in schizophrenia, particularly in immunity and synapse related pathways in pyramidal neurons, suggesting the disruption of these pathways plays an important role in schizophrenia. We also detected other pathways previously demonstrated in schizophrenia pathophysiology, including cytokine and chemotaxis, post-synaptic signaling, and glutamatergic synapses. In addition, we observed several novel pathways, including ubiquitin-independent protein catabolic process. We also used a bioinformatics approach to compare our differential expression gene profiles with 51 antipsychotic treatment datasets, demonstrating that our results were not influenced by antipsychotic treatment. Taken together, we found pyramidal neuron-specific changes in neuronal immunity, synaptic dysfunction, and olfactory dysregulation in schizophrenia, providing new insights for the cell-subtype specific pathophysiology of chronic schizophrenia.
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