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Molecular Mechanism for Stress-Induced Depression Assessed by Sequencing miRNA and mRNA in Medial Prefrontal Cortex

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      Abstract

      Background

      Major depression is a prevalent mood disorder. Chronic stress is presumably main etiology that leads to the neuron and synapse atrophies in the limbic system. However, the intermediate molecules from stresses to neuronal atrophy remain elusive, which we have studied in the medial prefrontal cortices from depression mice.

      Methods and Results

      The mice were treated by the chronic unpredictable mild stress (CUMS) until they expressed depression-like behaviors confirmed by the tests of sucrose preference, forced swimming and Y-maze. High-throughput sequencings of microRNA and mRNA in the medial prefrontal cortices were performed in CUMS-induced depression mice versus control mice to demonstrate the molecular profiles of major depression. In the medial prefrontal cortices of depression-like mice, the levels of mRNAs that translated the proteins for the GABAergic synapses, dopaminergic synapses, myelination, synaptic vesicle cycle and neuronal growth were downregulated. miRNAs of regulating these mRNAs are upregulated.

      Conclusion

      The deteriorations of GABAergic and dopaminergic synapses as well as axonal growth are associated with CUMS-induced depression.

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      Most cited references 80

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      Circular RNAs are a large class of animal RNAs with regulatory potency.

      Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.
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        miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades

        microRNAs (miRNAs) are a large class of small non-coding RNAs which post-transcriptionally regulate the expression of a large fraction of all animal genes and are important in a wide range of biological processes. Recent advances in high-throughput sequencing allow miRNA detection at unprecedented sensitivity, but the computational task of accurately identifying the miRNAs in the background of sequenced RNAs remains challenging. For this purpose, we have designed miRDeep2, a substantially improved algorithm which identifies canonical and non-canonical miRNAs such as those derived from transposable elements and informs on high-confidence candidates that are detected in multiple independent samples. Analyzing data from seven animal species representing the major animal clades, miRDeep2 identified miRNAs with an accuracy of 98.6–99.9% and reported hundreds of novel miRNAs. To test the accuracy of miRDeep2, we knocked down the miRNA biogenesis pathway in a human cell line and sequenced small RNAs before and after. The vast majority of the >100 novel miRNAs expressed in this cell line were indeed specifically downregulated, validating most miRDeep2 predictions. Last, a new miRNA expression profiling routine, low time and memory usage and user-friendly interactive graphic output can make miRDeep2 useful to a wide range of researchers.
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          Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types

          Most human pre-mRNAs are spliced into linear molecules that retain the exon order defined by the genomic sequence. By deep sequencing of RNA from a variety of normal and malignant human cells, we found RNA transcripts from many human genes in which the exons were arranged in a non-canonical order. Statistical estimates and biochemical assays provided strong evidence that a substantial fraction of the spliced transcripts from hundreds of genes are circular RNAs. Our results suggest that a non-canonical mode of RNA splicing, resulting in a circular RNA isoform, is a general feature of the gene expression program in human cells.
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            Author and article information

            Affiliations
            [1 ]Qingdao University, School of Pharmacy, Shandong, China
            [2 ]State Key Lab of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
            [3 ]University of Chinese Academy of Sciences, Beijing, China
            [4 ]College of Life Science, University of Science and Technology of China, Hefei, Anhui, China
            Chiba University Center for Forensic Mental Health, JAPAN
            Author notes

            Competing Interests: The authors have declared that no competing interests exist.

            Conceived and designed the experiments: JHW. Performed the experiments: KM LG AX SC. Analyzed the data: KM LG AX SC. Contributed reagents/materials/analysis tools: KM LG AX SC. Wrote the paper: JHW. Approved the final version of the manuscript: JHW KM LG AX SC.

            Contributors
            Role: Editor
            Journal
            PLoS One
            PLoS ONE
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, CA USA )
            1932-6203
            18 July 2016
            2016
            : 11
            : 7
            27427907 4948880 10.1371/journal.pone.0159093 PONE-D-16-12992
            © 2016 Ma et al

            This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Counts
            Figures: 2, Tables: 5, Pages: 21
            Product
            Funding
            Funded by: National Basic Research Program
            Award ID: 2013CB531304
            Award Recipient :
            Funded by: funder-id http://dx.doi.org/10.13039/100007847, Natural Science Foundation of Jilin Province;
            Award ID: 81471123
            Award Recipient :
            This study is granted by the National Basic Research Program (2013CB531304) and Natural Science Foundation China (81471123) to JHW.
            Categories
            Research Article
            Biology and life sciences
            Genetics
            Gene expression
            Gene regulation
            MicroRNAs
            Biology and life sciences
            Biochemistry
            Nucleic acids
            RNA
            Non-coding RNA
            MicroRNAs
            Medicine and Health Sciences
            Mental Health and Psychiatry
            Mood Disorders
            Depression
            Biology and life sciences
            Biochemistry
            Nucleic acids
            RNA
            Messenger RNA
            Biology and life sciences
            Molecular biology
            Molecular biology techniques
            Sequencing techniques
            RNA sequencing
            Research and analysis methods
            Molecular biology techniques
            Sequencing techniques
            RNA sequencing
            Biology and Life Sciences
            Organisms
            Animals
            Vertebrates
            Amniotes
            Mammals
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            Biology and Life Sciences
            Anatomy
            Nervous System
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            Medicine and Health Sciences
            Anatomy
            Nervous System
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            Biology and Life Sciences
            Physiology
            Electrophysiology
            Neurophysiology
            Synapses
            Medicine and Health Sciences
            Physiology
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            Neurophysiology
            Synapses
            Biology and Life Sciences
            Neuroscience
            Neurophysiology
            Synapses
            Biology and Life Sciences
            Genetics
            Gene Expression
            Biology and Life Sciences
            Anatomy
            Brain
            Prefrontal Cortex
            Medicine and Health Sciences
            Anatomy
            Brain
            Prefrontal Cortex
            Custom metadata
            The authors have registered with Genebank with the code GSE81590 to access their transcriptome and microRNA expression profiles.

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