HuD Regulates mRNA-circRNA-miRNA Networks in the Mouse Striatum Linked to Neuronal Development and Drug Addiction.
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ABSTRACT:
SUBMITTER: Dell'Orco M
PROVIDER: S-EPMC8468275 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The neuronal RNA-binding protein HuD is involved in synaptic plasticity and learning and memory mechanisms. These effects are thought to be due to HuD-mediated stabilization and translation of target mRNAs associated with plasticity. To investigate the potential role of HuD in drug addiction, we first used bioinformatics prediction algorithms together with microarray analyses to search for specific genes and functional networks upregulated within the forebrain of HuD overexpressing mice (HuDOE ). When this set was further limited to genes in the knowledgebase of addiction-related genes database (KARG) that contains predicted HuD-binding sites in their 3' untranslated regions (3'UTRs), we found that HuD regulates networks that have been associated with addiction-like behavior. These genes included Bdnf and Camk2a, 2 previously validated HuD targets. Since addiction is hypothesized to be a disorder stemming from altered gene expression causing aberrant plasticity, we sought to test the role of HuD in cocaine conditioned placed preference (CPP), a model of addiction-related behaviors. HuD mRNA and protein were upregulated by CPP within the nucleus accumbens of wild-type C57BL/6J mice. These changes were associated with increased expression of Bdnf and Camk2a mRNA and protein. To test this further, we trained HuDOE and wild-type mice in CPP and found that HuDOE mice showed increased cocaine CPP compared with controls. This was also associated with elevated expression of HuD target mRNAs and proteins, CaMKII? and BDNF. These findings suggest HuD involvement in addiction-related behaviors such as cocaine conditioning and seeking, through increased plasticity-related gene expression.
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Project description:Recent advances in sequencing technologies and the discovery of non-coding RNAs (ncRNAs) have provided new insights in the molecular pathogenesis of cancers. Several studies have implicated the role of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and recently discovered circular RNAs (circRNAs) in tumorigenesis and metastasis. Unlike linear RNAs, circRNAs are highly stable and closed-loop RNA molecules. It has been established that circRNAs regulate gene expression by controlling the functions of miRNAs and RNA-binding protein (RBP) or by translating into proteins. The circRNA-miRNA-mRNA regulatory axis is associated with human diseases, such as cancers, Alzheimer's disease, and diabetes. In this study, we explored the interaction among circRNAs, miRNAs, and their target genes in various cancers using state-of-the-art bioinformatics tools. We identified differentially expressed circRNAs, miRNAs, and mRNAs on multiple cancers from publicly available data. Furthermore, we identified many crucial drivers and tumor suppressor genes in the circRNA-miRNA-mRNA regulatory axis in various cancers. Together, this study data provide a deeper understanding of the circRNA-miRNA-mRNA regulatory mechanisms in cancers.
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Project description:Circular RNA (circRNA) is a novel type of endogenous noncoding RNA with covalently closed loop structures, which are widely expressed in various tissues and have functional implications in cellular processes. Acting as competing endogenous RNAs (ceRNAs), circRNAs are important regulators of miRNA activities. The identification of these circRNAs underlines the increasing complexity of ncRNA-mediated regulatory networks. However, more biological evidence is required to infer direct circRNA-miRNA associations while little attention has been paid to circRNAs in plants as compared to the abundant research in mammals. PlantCircNet is presented as an integrated database that provides visualized plant circRNA-miRNA-mRNA regulatory networks containing identified circRNAs in eight model plants. The bioinformatics integration of data from multiple sources reveals circRNA-miRNA-mRNA regulatory networks and helps identify mechanisms underlying metabolic effects of circRNAs. An enrichment analysis tool was implemented to detect significantly overrepresented Gene Ontology categories of miRNA targets. The genomic annotations, sequences and isoforms of circRNAs were also investigated. PlantCircNet provides a user-friendly interface for querying detailed information of specific plant circRNAs. The database may serve as a resource to facilitate plant circRNA research. Several circRNAs were identified to play potential regulatory roles in flower development and response to environmental stress from regulatory networks related with miR156a and AT5G59720, respectively. This present research indicated that circRNAs could be involved in diverse biological processes. Database URL: http://bis.zju.edu.cn/plantcircnet/index.php.
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Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and severe side effect of first-line chemotherapeutic agents. The association between circular RNAs (circRNAs) and CIPN remains unclear. In this study, CIPN models were constructed with Taxol, while 134 differentially expressed circRNAs, 353 differentially expressed long non-coding RNAs, and 86 differentially expressed messenger RNAs (mRNAs) were identified utilizing RNA sequencing. CircRNA-targeted microRNAs (miRNAs) were predicted using miRanda, and miRNA-targeted mRNAs were predicted using TargetScan and miRDB. The intersection of sequencing and mRNA prediction results was selected to establish the circRNA-miRNA-mRNA networks, which include 15 circRNAs, 18 miRNAs, and 11 mRNAs. Functional enrichment pathway analyses and immune infiltration analyses revealed that differentially expressed mRNAs were enriched in the immune system, especially in T cells, monocytes, and macrophages. Cdh1, Satb2, Fas, P2ry2, and Zfhx2 were further identified as hub genes and validated by RT-qPCR, correlating with macrophages, plasmacytoid dendritic cells, and central memory CD4 T cells in CIPN. Additionally, we predicted the associated diseases, 36 potential transcription factors (TFs), and 30 putative drugs for hub genes using the DisGeNET, TRRUST, and DGIdb databases, respectively. Our results indicated the crucial role of circRNAs, and the immune microenvironment played in CIPN, providing novel insights for further research.
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Project description:Coxsackievirus A16 (CV-A16) has caused worldwide epidemics of hand, foot, and mouth disease (HFMD) in infants and preschool children. Circular RNAs (circRNAs), a class of noncoding RNA molecules, participate in the progression of viral infectious diseases. Although the function of circRNAs has been a heavily researched topic, their role in CV-A16 infection is still unclear. In this study, the viral effects of CV-A16 on the cellular circRNA transcriptome were investigated using next-generation sequencing technology. The results showed that a total of 8726, 8611, and 6826 circRNAs were identified at 0, 12, and 24 h postinfection, respectively. Moreover, it was found that 1769 and 1192 circRNAs were differentially expressed in at 12 and 24 h postinfection, respectively. The common differentially expressed circRNAs were used for functional annotation analysis, and it was found that the parent genes of differentially expressed circRNAs might be associated with the viral infection process, especially the "Immune system process" in GO analysis and the "Inflammation mediated by chemokine and cytokine signaling pathway" in KEGG analysis. Subsequently, circRNA-miRNA-mRNA regulatory networks were constructed, and the hsa_circ_0004447/hsa-miR-942-5p/MMP2, hsa_circ_0078617/hsa-miR-6780b-5p/MMP2 and hsa_circ_0078617/hsa-miR-5196-5p/MMP2 regulatory axes were identified by enrichment analysis as important networks during the progression of CV-A16 infection. Finally, six dysregulated circRNAs were selected for validation and were verified to be consistent with the sequencing results. Considering all of these results, to the best of our knowledge, this study is the first to present a comprehensive overview of circRNAs induced by CV-A16 infection, and this research demonstrated that a network of enriched circRNAs and circRNA-associated competitive endogenous RNAs (ceRNAs) is involved in the regulation of CV-A16 infection, thereby helping to elucidate the mechanisms underlying CV-A16-host interactions.
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Project description:Osteoarthritis (OA) is a common orthopedic degenerative disease, leading to high disability in activities of daily living. There remains an urgent need to identify the underlying mechanisms and identify new therapeutic targets in OA diagnosis and treatment. Circular RNAs (circRNAs) play a role in the development of multiple diseases. Many studies have reported that circRNAs regulate microRNAs (miRNAs) through an endogenous competitive mechanism. However, it remains unclear if an interplay between circRNAs, miRNAs, and target genes plays a deeper regulatory role in OA. Four datasets were downloaded from the GEO database, and differentially expressed circRNAs (DECs), differentially expressed miRNAs (DEMs), and differentially expressed genes (DEGs) were identified. Functional annotation and pathway enrichment analysis of DEGs and DECs were carried out to determine the main associated mechanism in OA. A protein–protein network (PPI) was constructed to analyze the function of, and to screen out, hub DEGs in OA. Based on the artificial intelligence prediction of protein crystal structures of two hub DEGs, TOP2A and PLK1, digitoxin and oxytetracycline were found to have the strongest affinity, respectively, with molecular docking. Subsequently, overlapping DEMs and miRNAs targeted by DECs obtained target DEMs (DETMs). Intersection of DEGs and genes targeted by DEMs obtained target DEGs (DETGs). Thus, a circRNA–miRNA–mRNA regulatory network was constructed from 16 circRNAs, 32 miRNAs, and 97 mRNAs. Three hub DECs have the largest number of regulated miRNAs and were verified through in vitro experiments. In addition, the expression level of 16 DECs was validated by RT-PCR. In conclusion, we constructed a circRNA–miRNA–mRNA regulatory network in OA and three new hub DECs, hsa_circ_0027914, hsa_circ_0101125, and hsa_circ_0102564, were identified as novel biomarkers for OA.
| S-EPMC9869167 | biostudies-literature
Project description:The generation and differentiation of B lymphocytes (B cells) is a flexible process with many critical regulatory factors. Previous studies indicated that non-coding RNAs play multiple roles in the development of lymphocytes. However, little has been known about the circular RNA (circRNA) profiles and their competing endogenous RNA (ceRNA) networks in B-cell development and differentiation. Here, four B-cell subsets were purified from single-cell suspensions of mouse bone marrow. Then RNA sequencing (RNA-Seq) was used to display expression profiles of circRNAs, miRNAs and mRNAs during B-cell differentiation. 175, 203, 219 and 207 circRNAs were specifically expressed in pro-B cells, pre-B cells, immature B cells and mature B cells, respectively. The circRNA-associated ceRNA networks constructed in two sequential stages of B-cell differentiation revealed the potential mechanism of circRNAs in these processes. This study is the first to explore circRNA profiles and circRNA-miRNA-mRNA networks in different B-cell developmental stages of mouse bone marrow, which contribute to further research on their mechanism in B-cell development and differentiation.
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Project description:Our lab and others have shown that chronic alcohol use leads to gene and miRNA expression changes across the mesocorticolimbic (MCL) system. Circular RNAs (circRNAs) are noncoding RNAs that form closed-loop structures and are reported to alter gene expression through miRNA sequestration, thus providing a potentially novel neurobiological mechanism for the development of alcohol dependence (AD). Genome-wide expression of circRNA was assessed in the nucleus accumbens (NAc) from 32 AD-matched cases/controls. Significant circRNAs (unadj. p ≤ 0.05) were identified via regression and clustered in circRNA networks via weighted gene co-expression network analysis (WGCNA). CircRNA interactions with previously generated mRNA and miRNA were detected via correlation and bioinformatic analyses. Significant circRNAs (N = 542) clustered in nine significant AD modules (FWER p ≤ 0.05), within which we identified 137 circRNA hubs. We detected 23 significant circRNA-miRNA-mRNA interactions (FDR ≤ 0.10). Among these, circRNA-406742 and miR-1200 significantly interact with the highest number of mRNA, including genes associated with neuronal functioning and alcohol addiction (HRAS, PRKCB, HOMER1, and PCLO). Finally, we integrate genotypic information that revealed 96 significant circRNA expression quantitative trait loci (eQTLs) (unadj. p ≤ 0.002) that showed significant enrichment within recent alcohol use disorder (AUD) and smoking genome-wide association study (GWAS). To our knowledge, this is the first study to examine the role of circRNA in the neuropathology of AD. We show that circRNAs impact mRNA expression by interacting with miRNA in the NAc of AD subjects. More importantly, we provide indirect evidence for the clinical importance of circRNA in the development of AUD by detecting a significant enrichment of our circRNA eQTLs among GWAS of substance abuse.
| S-EPMC8590811 | biostudies-literature
Project description:Gastrointestinal stromal tumours (GISTs) are the most common human sarcomas and are typically located in the stomach or small intestine. Although circular RNAs (circRNAs) reportedly play vital roles in tumour oncogenesis and progression, the molecular basis of the aggressive tumour biology of these circRNAs in GISTs remains unclear. In this study, we applied SBC ceRNA microarrays to screen for tumour-specific circRNA profiles in GISTs and identified that a total of 5,770 circRNAs and 1,815 mRNAs were differentially expressed in GISTs. Three significantly differential circRNAs (circ_0069765, circ_0084097, and circ_0079471) and their host genes (KIT, PLAT, and ETV1) were also verified in 68 pairs of GISTs and adjacent normal gastrointestinal tissues by qRT-PCR. A GIST-specific circRNA-miRNA-mRNA regulatory network analysis demonstrated that the specific KIT-related regulatory networks involved the three circRNAs, the circRNA host genes and three miRNAs (miR-142-5p, miR-144-3p and miR-485-3p), which may be key regulators of GISTs that could serve as molecular biomarkers and potential therapeutic targets for this malignant disease.
| S-EPMC6746987 | biostudies-literature
Project description:Background:Circular RNAs (circRNAs) were elucidated to act as competing endogenous RNAs (ceRNAs) and to play significant roles in cancer initiation and progression. We aimed to identify the important circRNAs in lung adenocarcinoma and intended to predict the functions of them via the bioinformatics analysis. Methods:We extracted data from three Gene Expression Omnibus (GEO) datasets, GSE101586, GSE101684, and GSE104854, and identified the common differentially expressed circRNAs. Agarose gel electrophoresis and Sanger sequencing were used to verify these significant circRNAs. Then, qRT-PCR was performed to validate the expression through matched tissues and cell lines. Afterwards, a ceRNA network was constructed and functional analysis was performed to predict the potential mechanisms of circRNAs. Results:Five circRNAs (hsa_circ_0072088, hsa_circ_0082564, hsa_circ_0008274, hsa_circ_0000519 and hsa_circ_0003528) were identified differentially expressed in the three datasets. Following the Agarose gel electrophoresis and qRT-PCR validation, hsa_circ_0072088 and hsa_circ_0008274 were chosen for further analysis. A ceRNA network of hsa_circ_0072088 and hsa_circ_0008274 was built based on the CSCD/TargetScan/MiRTarbase/StarBase 3.0. Then, the functional analysis showed that several meaningful terms were identified, such as "epithelial to mesenchymal transition (EMT)", "Cellular response to TGF-? stimulus", "MAPK signaling pathway", and "PI3K-AKT signaling pathway". Finally, several significant circRNA/miRNA/mRNA regulatory axes, which were predicted relating to cancer progress, were noted from the network. Conclusion:We identified significant circRNAs and meaningful circRNA-miRNA-mRNA networks to provide novel insight into pathogenesis and therapy of lung adenocarcinoma.
| S-EPMC7152915 | biostudies-literature