The miR-92a–Cpeb3 axis safeguards neuronal function during neuroinflammation
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ABSTRACT:
PROVIDER: PRJNA912144 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22731201.fastq.gz | Fastqsanger.gz | |||
| SRR22731202.fastq.gz | Fastqsanger.gz | |||
| SRR22731203.fastq.gz | Fastqsanger.gz | |||
| SRR22731204.fastq.gz | Fastqsanger.gz | |||
| SRR22731205.fastq.gz | Fastqsanger.gz |
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Project description:Neuroinflammation causes neuronal injury in multiple sclerosis (MS) and other neurological diseases. MicroRNAs (miRNAs) are central modulators of cellular stress responses, but knowledge about miRNA–mRNA interactions that determine neuronal outcome during inflammation is limited. Here, we combined unbiased neuron-specific miRNA with mRNA sequencing to assemble the regulatory network that mediates robustness against neuroinflammation. As a critical miRNA-network hub we defined miR-92a. Genetic deletion of miR-92a exacerbated the disease course of mice undergoing experimental autoimmune encephalomyelitis (EAE), whereas miR-92a overexpression protected neurons against excitotoxicity. As a key miR-92a target transcript, we identified cytoplasmic polyadenylation element-binding protein 3 (Cpeb3) that was suppressed in inflamed neurons in mouse EAE and human MS. Accordingly, Cpeb3 deletion improved neuronal resistance to excitotoxicity and ameliorated EAE. Together, we discovered that the miR-92a–Cpeb3 axis confers neuronal robustness against inflammation and serves as potential target for neuroprotective therapies.
2023-11-06 | GSE220950 | GEO
Project description:Neuroinflammation causes neuronal injury in multiple sclerosis (MS) and other neurological diseases. MicroRNAs (miRNAs) are central modulators of cellular stress responses, but knowledge about miRNA–mRNA interactions that determine neuronal outcome during inflammation is limited. Here, we combined unbiased neuron-specific miRNA with mRNA sequencing to assemble the regulatory network that mediates robustness against neuroinflammation. As a critical miRNA-network hub we defined miR-92a. Genetic deletion of miR-92a exacerbated the disease course of mice undergoing experimental autoimmune encephalomyelitis (EAE), whereas miR-92a overexpression protected neurons against excitotoxicity. As a key miR-92a target transcript, we identified cytoplasmic polyadenylation element-binding protein 3 (Cpeb3) that was suppressed in inflamed neurons in mouse EAE and human MS. Accordingly, Cpeb3 deletion improved neuronal resistance to excitotoxicity and ameliorated EAE. Together, we discovered that the miR-92a–Cpeb3 axis confers neuronal robustness against inflammation and serves as potential target for neuroprotective therapies.
2023-11-06 | GSE224558 | GEO
Project description:Cpeb3 knockout cortical neuronal cultures
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Project description:In the mammalian brain, alternative pre-mRNA splicing is a fundamental mechanism that modifies neuronal function dynamically where secretion of different splice variants regulates neurogenesis, development, pathfinding, maintenance, migration, and synaptogenesis. Sequence-specific RNA Binding Protein CPEB3 has distinctive isoform-distinct biochemical interactions and neuronal development assembly roles. Nonetheless, the mechanisms moderating splice isoform options remain unclear. To establish the modulatory trend of CPEB3, we cloned and excessively expressed CPEB3 in HT22 cells. We used RNA-seq to analyze CPEB3-regulated alternative splicing on control and CPEB3-overexpressing cells. Moreover, we used iRIP-seq to identify CPEB-binding targets. We additionally validated CPEB3-modulated genes using RT-qPCR. CPEB3 overexpression had insignificant effects on gene expression in HT22 cells. Notably, CPEB3 partially modulated differential gene splicing enhanced in the modulation of transcription, cell cycle, Wnt signaling cascade, neurotrophin, synapse, and specific development pathway. qRT‑PCR verified the CPEB3‑modulated transcription of neurogenesis genes LCN2 and NAV2, synaptogenesis gene CYLD, as well as development gene JADE1. Herein, we established that CPEB3 is a critical modulator of alternative splicing in neurogenesis, which remarkably enhances the current understanding of the CPEB3 mediated alternative pre-mRNA splicing.
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Project description:In the mammalian brain, alternative pre-mRNA splicing is a fundamental mechanism that modifies neuronal function dynamically where secretion of different splice variants regulates neurogenesis, development, pathfinding, maintenance, migration, and synaptogenesis. Sequence-specific RNA Binding Protein CPEB3 has distinctive isoform-distinct biochemical interactions and neuronal development assembly roles. Nonetheless, the mechanisms moderating splice isoform options remain unclear. To establish the modulatory trend of CPEB3, we cloned and excessively expressed CPEB3 in HT22 cells. We used RNA-seq to analyze CPEB3-regulated alternative splicing on control and CPEB3-overexpressing cells. Moreover, we used iRIP-seq to identify CPEB-binding targets. We additionally validated CPEB3-modulated genes using RT-qPCR. CPEB3 overexpression had insignificant effects on gene expression in HT22 cells. Notably, CPEB3 partially modulated differential gene splicing enhanced in the modulation of transcription, cell cycle, Wnt signaling cascade, neurotrophin, synapse, and specific development pathway. qRT‑PCR verified the CPEB3‑modulated transcription of neurogenesis genes LCN2 and NAV2, synaptogenesis gene CYLD, as well as development gene JADE1. Herein, we established that CPEB3 is a critical modulator of alternative splicing in neurogenesis, which remarkably enhances the current understanding of the CPEB3 mediated alternative pre-mRNA splicing.
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Project description:Mammalian oocyte development depends on the temporally controlled translation of maternal transcripts, particularly in the coordination of meiotic and early embryonic development when transcription has ceased. The translation of mRNA is regulated by various RNA-binding proteins. We show that the absence of cytoplasmic polyadenylation element-binding protein 3 (CPEB3) neg-atively affects female reproductive fitness. CPEB3-depleted oocytes undergo meiosis normally but experience early embryonic arrest due to a disrupted transcriptome, leading to aberrant protein expression and the subsequent failure of embryonic transcription initiation. We found that CPEB3 stabilizes a subset of mRNAs with a significantly longer 3’UTR that is enriched in its distal region with cytoplasmic polyadenylation elements. Overall, our results suggest that CPEB3 is an im-portant maternal factor that regulates the stability and translation of a subclass of mRNAs that are essential for the initiation of embryonic transcription and thus for embryonic development.
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Project description:CPEB3 inhibits a cluster of signaling pathways associated with tumor progression. Gene expression profiling analysis was performed to identify the potential pathways of CPEB3.
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Project description:Susceptibility or resilience to posttraumatic stress disorder (PTSD) depends on one’s ability to appropriately adjust synaptic plasticity for coping with the traumatic experience. Activity-regulated mRNA translation synthesizes plasticity-related proteins to support long-term synaptic changes and memory. Hence, cytoplasmic polyadenylation element-binding protein 3-knockout (CPEB3-KO) mice, showing dysregulated translation-associated synaptic rigidity, may be susceptible to PTSD-like behavior. Here, using a context-dependent auditory fear conditioning and extinction paradigm, we found that CPEB3-KO mice exhibited traumatic intensity-dependent PTSD-like fear memory. A genome-wide screen of CPEB3-bound transcripts revealed that Nr3c1, encoding glucocorticoid receptor (GR), was translationally suppressed by CPEB3. Thus, CPEB3-KO neurons with elevated GR expression exhibited increased corticosterone-induced calcium influx and decreased mRNA and protein levels of brain-derived neurotrophic factor (Bdnf). Moreover, the reduced expression of BDNF was associated with increased GR level during fear extinction in CPEB3-KO hippocampi. Intracerebroventricular delivery of BDNF before extinction training mitigated spontaneous fear intrusion in CPEB3-KO mice during extinction recall. Analysis of two GEO datasets revealed decreased transcriptomic expression of CPEB3 but not NR3C1 in peripheral blood mononuclear cells of humans with PTSD. Collectively, this study reveals that CPEB3, as a potential PTSD-risk gene, downregulates Nr3c1 translation to maintain proper GR-BDNF signaling for fear extinction.
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