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Circular RNA biogenesis is decreased in postmortem cortical gray matter in schizophrenia and may alter the bioavailability of associated miRNA.

ABSTRACT: Circular RNAs (circRNAs) are a covalently closed subclass of non-coding RNA molecules formed by back splicing of linear precursor RNA. These molecules are relatively stable and particularly abundant in the mammalian brain and therefore may participate in neural development and function. With the emergence of circRNAs activity in gene regulation, these molecules have been implicated in several biological processes, including synaptic plasticity, and we therefore suspect they may have a role in neurobehavioral disorders. Here, we profile cortical circRNAs expression in 35 postmortem cortical gray matter (BA46) schizophrenia and a non-psychiatric comparison group, using circRNA enrichment sequencing. While more than 90,000 circRNAs species were identified in the dorsolateral prefrontal cortex (DLPFC), we observed lower complexity and substantial depletion in subjects with the disorder. Although circRNAs expression was independent of their host gene transcription, alternative splicing rates were lower in samples from cases compared to controls. Gene set analysis of differentially expressed circRNAs host genes revealed significant enrichment of neural functions and neurological disorders. Many of these depleted circRNAs are also predicted to sequester miRNAs that were shown previously to be increased in the disorder, potentially exacerbating the functional impact of their dysregulation through posttranscriptional gene silencing. While this is the first reported exploration of circRNAs in schizophrenia, there is significant potential for dysregulation more broadly in other major mental illnesses and behavioral disorders. Given their capacity for modulating miRNA function, circRNA may play a significant role in the pathophysiology of disease and even be targeted for therapeutic manipulation.

SUBMITTER: Mahmoudi E

PROVIDER: S-EPMC6461776 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Circular RNA biogenesis is decreased in postmortem cortical gray matter in schizophrenia and may alter the bioavailability of associated miRNA.

Mahmoudi Ebrahim E Fitzsimmons Chantel C Geaghan Michael P MP Shannon Weickert Cynthia C Atkins Joshua R JR Wang Xi X Cairns Murray J MJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190220 6

Circular RNAs (circRNAs) are a covalently closed subclass of non-coding RNA molecules formed by back splicing of linear precursor RNA. These molecules are relatively stable and particularly abundant in the mammalian brain and therefore may participate in neural development and function. With the emergence of circRNAs activity in gene regulation, these molecules have been implicated in several biological processes, including synaptic plasticity, and we therefore suspect they may have a role in ne ...[more]

PMID: 30786269

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Project description:IntroductionWe performed a whole-transcriptome correlation analysis, followed by the pathway enrichment and testing of innate immune response pathway analyses to evaluate the hypothesis that transcriptional activity can predict cortical gray matter thickness (GMT) variability during normal cerebral aging.MethodsTranscriptome and GMT data were available for 379 individuals (age range=28-85) community-dwelling members of large extended Mexican American families. Collection of transcriptome data preceded that of neuroimaging data by 17 years. Genome-wide gene transcriptome data consisted of 20,413 heritable lymphocytes-based transcripts. GMT measurements were performed from high-resolution (isotropic 800 ?m) T1-weighted MRI. Transcriptome-wide and pathway enrichment analysis was used to classify genes correlated with GMT. Transcripts for sixty genes from seven innate immune pathways were tested as specific predictors of GMT variability.ResultsTranscripts for eight genes (IGFBP3, LRRN3, CRIP2, SCD, IDS, TCF4, GATA3, and HN1) passed the transcriptome-wide significance threshold. Four orthogonal factors extracted from this set predicted 31.9% of the variability in the whole-brain and between 23.4 and 35% of regional GMT measurements. Pathway enrichment analysis identified six functional categories including cellular proliferation, aggregation, differentiation, viral infection, and metabolism. The integrin signaling pathway was significantly (p<10(-6)) enriched with GMT. Finally, three innate immune pathways (complement signaling, toll-receptors and scavenger and immunoglobulins) were significantly associated with GMT.ConclusionExpression activity for the genes that regulate cellular proliferation, adhesion, differentiation and inflammation can explain a significant proportion of individual variability in cortical GMT. Our findings suggest that normal cerebral aging is the product of a progressive decline in regenerative capacity and increased neuroinflammation.

Project description:IntroductionNicotine dependence (ND) is a chronic, relapsing mental disorder characterized by compulsive cigarette seeking and smoking. Although the cerebellum plays an increasingly implicated role in ND, the exact cerebellar alterations in ND remain unclear. Identifying the localization of these cerebellar abnormalities in ND may help to further understand the role of the cerebellum in ND. Thus, we investigated the structural and functional alterations in the cerebellum in a large sample of smokers using the spatially unbiased infratentorial template (SUIT).MethodsHigh-resolution structural magnetic resonance imaging (MRI) data were acquired from 85 smokers and 41 nonsmokers. We applied voxel-based morphometry (VBM) and the SUIT cerebellar atlas to compare the cerebellar gray matter (GM) volume between smokers and nonsmokers. Using resting-state functional MRI data, we also performed seed-based functional connectivity (FC) analysis to examine the functional correlates of the GM volume changes.ResultsBoth VBM and lobular analyses revealed smaller GM volume in the bilateral Crus I in smokers. The GM volume of the left Crus I was inversely correlated with the severity of nicotine dependence as assessed by Fagerström Test for Nicotine Dependence (r = -.268, p = .013). We also found reduced FC between the bilateral Crus I and brain regions involved in the default mode network and motor system, as well as the frontal and temporal cortex in smokers.ConclusionsOur results indicate that decreased cerebellar GM volume and corticocerebellar FC are associated with ND, and these may underlie the core ND phenotypes, including automatized smoking behavior, cognitive, and emotional deficits.ImplicationsAs smoking remains a worldwide public health problem, identifying the related neural alterations may help to understand the pathophysiology of ND. Based on previous findings in the cerebellum, we investigated the localization of the GM differences and related FC changes in ND subjects. Our findings highlight altered corticocerebellar circuits in ND, suggesting an association between the cerebellum and the phenotypes of ND.

Dataset Information

Circular RNA biogenesis is decreased in postmortem cortical gray matter in schizophrenia and may alter the bioavailability of associated miRNA.

Publications

Circular RNA biogenesis is decreased in postmortem cortical gray matter in schizophrenia and may alter the bioavailability of associated miRNA.

Similar Datasets

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