Microarray Profiling and Co-Expression Network Analysis of LncRNAs and mRNAs in Neonatal Rats Following Hypoxic-ischemic Brain Damage.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhao F
PROVIDER: S-EPMC4563552 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:LncRNAs, which represent one of the most highly expressed classes of ncRNAs in the brain, are becoming increasingly interesting with regard to brain functions and disorders. However, changes in the expression of regulatory lncRNAs in Major Depressive Disorder (MDD) have not yet been reported. Using microarrays, we profiled the expression of 34834 lncRNAs and 39224 mRNAs in peripheral blood sampled from MDD patients as well as demographically-matched controls. Among these, we found that 2007 lncRNAs and 1667 mRNAs were differentially expressed, 17 of which were documented as depression-related gene in previous studies. Gene Ontology (GO) and pathway analyses indicated that the biological functions of differentially expressed mRNAs were related to fundamental metabolic processes and neurodevelopment diseases. To investigate the potential regulatory roles of the differentially expressed lncRNAs on the mRNAs, we also constructed co-expression networks composed of the lncRNAs and mRNAs, which shows significant correlated patterns of expression. In the MDD-derived network, there were a greater number of nodes and connections than that in the control-derived network. The lncRNAs located at chr10:874695-874794, chr10:75873456-75873642, and chr3:47048304-47048512 may be important factors regulating the expression of mRNAs as they have previously been reported associations with MDD. This study is the first to explore genome-wide lncRNA expression and co-expression with mRNA patterns in MDD using microarray technology. We identified circulating lncRNAs that are aberrantly expressed in MDD and the results suggest that lncRNAs may contribute to the molecular pathogenesis of MDD.
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Project description:BackgroundFew studies on the consequences following newborn hypoxic-ischemic encephalopathy (NHIE) assess the risk of mood disorders (MD), although these are prevalent after ischemic brain injury in adults.ObjectiveTo study the presence of MD in children survivors of NHIE.Methods14 children survivors of NHIE treated with hypothermia and without cerebral palsy and 15 healthy children without perinatal complications were studied aged three to six years for developmental status (Ages and Stages Questionnaire 3 [ASQ-3]) and for socio-emotional status (Preschool Symptom Self-Report [PRESS] and Child Behavior Checklist [CBCL] 1.5-5 tests). Maternal depression was assessed using Montgomery-Asberg Depression Rating Scale (MADRS). Socio-economic factors such as parental educational level or monthly income were also studied.ResultsNHIE children did not present delay but scored worse than healthy children for all ASQ3 items. NHIE children showed higher scores than healthy children for PRESS as well as for anxious/depressive symptoms and aggressive behavior items of CBCL. In addition, in three NHIE children the CBCL anxious/depressive symptoms item score exceeded the cutoff value for frank pathology (P = 0.04 vs healthy children). There were no differences in the other CBCL items as well as in maternal MADRS or parental educational level or monthly income. Neither ASQ3 scores nor MADRS score or socio-economic factors correlated with PRESS or CBCL scores.ConclusionsIn this exploratory study children survivors of NHIE showed increased risk of developing mood disturbances, in accordance with that reported for adults after brain ischemic insults. Considering the potential consequences, such a possibility warrants further research.
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Project description:Secondary brain damage caused by hyperactivation of autophagy and inflammatory responses in neurons plays an important role in hypoxic-ischemic brain damage (HIBD). Although previous studies have implicated Toll-like receptor 4 (TLR4) and nuclear factor kappa-B (NF-κB) in the neuroinflammatory response elicited by brain injury, the role and mechanisms of the TLR4-mediated autophagy signaling pathway in neonatal HIBD are still unclear. We hypothesized that this pathway can regulate brain damage by modulating neuron autophagy and neuroinflammation in neonatal rats with HIBD. Hence, we established a neonatal HIBD rat model using the Rice-Vannucci method, and injected 0.75, 1.5, or 3 mg/kg of the TLR4 inhibitor resatorvid (TAK-242) 30 minutes after hypoxic ischemia. Our results indicate that administering TAK-242 to neonatal rats after HIBD could significantly reduce the infarct volume and the extent of cerebral edema, alleviate neuronal damage and neurobehavioral impairment, and decrease the expression levels of TLR4, phospho-NF-κB p65, Beclin-1, microtubule-associated protein l light chain 3, tumor necrosis factor-α, and interleukin-1β in the hippocampus. Thus, TAK-242 appears to exert a neuroprotective effect after HIBD by inhibiting activation of autophagy and the release of inflammatory cytokines via inhibition of the TLR4/NF-κB signaling pathway. This study was approved by the Laboratory Animal Ethics Committee of Affiliated Hospital of Yangzhou University, China (approval No. 20180114-15) on January 14, 2018.
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Project description:LncRNAs abundantly expressed in the brain have vital and wide-ranging functions in different biological processes. However, little is currently known regarding the influence of lncRNAs in developing brains after hypoxic-ischemic brain damage (HIBD). In this study, to investigate the lncRNAs expression signatures and the co-expression network of lncRNAs and mRNAs in the brain after HIBD, we established a neonatal rat HIBD model and detected the expression profiles of lncRNAs in the HIBD brain and a sham control using high-throughput sequencing. Further, highly differentially expressed lncRNAs were selected and validated by qRT-PCR. Finally, the biological functions of the selected lncRNAs were investigated by over-expressing or silencing the target genes through lentivirus transfection in hippocampal neuron cells. Our results revealed that the expression profile of lncRNAs was dramatically different between the HIBD brains and the sham control, showing as the aberrant expression of 617 lncRNA transcripts and 441 mRNA transcripts at 24 hours after HIBD. GO and KEGG analyses indicated that the differentially expressed mRNAs were mostly involved in the apoptosis signaling pathway. After validating the expression of 8 randomly selected lncRNA transcripts by qRT-PCR, we found that the TNFRSF17 gene (ID: ENSRNOG00000021987) was down-regulated in HI brains. After stable over-expression and silencing of TNFRSF17, the apoptosis rate of hippocampal neuron cells exhibited obvious changes under hypoxia or normaxia. The over-expression of TNFRSF17 could significantly up-regulate Bcl-2 but down-regulate Bax, caspase-3, and caspase-9 at the mRNA and protein levels, while the silencing of TNFRSF17 led to just the opposite phenomenon. Notably, the regulation effects of TNFRSF17 on apoptotic related genes and proteins under hypoxia were more obvious than those under normaxia. Moreover, the over-expression of TNFRSF17 reduced the apoptotic rate, but the loss of TNFRSF17 led to a high rate of apoptosis under hypoxia. Taken together, the silencing of TNFRSF17 exacerbated, while over-expression attenuated, neuron apoptosis induced by HI injury, suggesting that TNFRSF17 may be a target for the prognosis, diagnosis, and treatment of HIBD.
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Project description:Subarachnoid haemorrhage (SAH) is a fatal neurovascular disease following cerebral aneurysm rupture with high morbidity and mortality rates. Long non-coding RNAs (lncRNAs) are a type of mammalian genome transcript, are abundantly expressed in the brain and are involved in many nervous system diseases. However, little is currently known regarding the influence of lncRNAs in early brain injury (EBI) after SAH. This study analysed the expression profiles of lncRNAs and mRNAs in SAH brain tissues of mice using high-throughput sequencing. The results showed a remarkable difference in lncRNA and mRNA transcripts between SAH and control brains. Approximately 617 lncRNA transcripts and 441 mRNA transcripts were aberrantly expressed at 24?hours after SAH. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the differentially expressed mRNAs were mostly involved in inflammation. Based on the lncRNA/mRNA co-expression network, knockdown of fantom3_F730004F19 reduced the mRNA and protein levels of CD14 and toll-like receptor 4 (TLR4) and attenuated inflammation in BV-2 microglia cells. These results indicate that lncRNA fantom3_F730004F19 may be associated with microglia induced inflammation via the TLR signaling pathway in EBI following SAH. LncRNA represent a potential therapeutic target for the prognosis, diagnosis, and treatment of SAH.
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Project description:Venous congestion and volume overload are important in cardiorenal syndromes, in which multiple regulated factors are involved, including long non‑coding RNAs (lncRNAs). To investigate the underlying role of lncRNAs in regulating the development of venous congestion, an Affymetrix microarray associated with peripheral venous congestion was annotated, then a bipartite dynamic lncRNA-mRNA co-expression network was constructed in which nodes indicated lncRNAs or mRNAs. The nodes were connected when the lncRNAs or mRNAs were dynamically co‑expressed. Following functional analysis of this network, several dynamic alternative pathways were identified, including the calcium signaling pathway during venous congestion development. Additionally, certain lncRNAs (LINC00523, LINC01210 and RP11-435O5.5) were identified that may potentially dynamically regulate certain proteins, including plasma membrane calcium ATPase (PMCA) and G protein‑coupled receptor (GPCR), in the calcium signaling pathway. Particularly, the dynamically regulated switch of LINC00523 from co‑expression with PMCA to GPCR may be involved in damage to steady state intracellular calcium. In brief, the current study demonstrated a potential novel mechanism of lncRNA function during venous congestion.
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Project description:Mesenchymal stem cells (MSCs) have been shown to improve outcomes after neonatal hypoxic-ischemic (HI) brain injury possibly by secretion of growth factors stimulating repair processes. We investigated whether MSCs, modified to secrete specific growth factors, can further enhance recovery. Using an in vitro assay, we show that MSC-secreting brain derived neurotrophic factor (BDNF), epidermal growth factor-like 7 (EGFL7), persephin (PSP), or sonic hedgehog (SHH) regulate proliferation and differentiation of neural stem cells. Moreover, mice that received an intranasal application of 100,000 MSC-BDNF showed significantly improved outcomes as demonstrated by improved motor function and decreased lesion volume compared with mice treated with empty vector (EV) MSCs. Treatment with MSC-EGFL7 improved motor function but had no effect on lesion size. Treatment with MSC-PSP or MSC-SHH neither improved outcome nor reduced lesion size in comparison with MSC-EV-treated mice. Moreover, mice treated with MSC-SHH showed even decreased functional outcomes when compared with those treated with MSC-EV. Treatment with MSC-BDNF induced cell proliferation in the ischemic hemisphere lasting at least 18 days after MSC administration, whereas treatment with MSC-EV did not. These data suggest that gene-modified cell therapy might be a useful approach to consider for treatment of neonatal HI brain damage. However, care must be taken when selecting the agent to overexpress.
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Project description:Neonatal brain hypoxic ischemic injury is a devastating event causing permanent brain damage. The current study set out to explore the role of Kruppel-like factor 2 (KLF2) and its downstream molecular mechanism on hypoxic-ischemic brain damage (HIBD) in neonatal rats. First, we adopted a modified Rice method to develop a HIBD model in postnatal day seven Sprague Dawley (SD) rat pups. Next, neuronal damage, morphological changes, and neuronal apoptosis were documented in the vulnerable hippocampal CA1 region and evaluated using Nissl staining, H&E staining, and TUNEL assay, respectively. Meanwhile, a hypoxic-ischemic model using the oxygen-glucose deprivation (OGD) method was established in cortical neurons isolated from day one SD rat pups, followed by MTT and flow cytometry detections of the cell survival rate and apoptotic ability. Experimental findings revealed that KLF2 was poorly-expressed in the brain tissues of HIBD rats and in the OGD-induced neurons. We found that KLF2 overexpression inhibited neuron apoptosis in vitro and in vivo, which was also observed to inhibit brain injury in the HIBD rats and alleviate neuronal damage of OGD-treated neurons. Besides, as dual luciferase reporter gene assay and chromatin immunoprecipitation established that KLF2 bound to the interferon regulatory factor 4 (IRF4) promoter, which promoted the binding of IRF4 in the promoter of histone deacetylase 7 (HDAC7) to augment its expression, thereby inhibiting neuronal apoptosis and brain damage. In conclusion, our findings indicated that KLF2 could increase the expression of IRF4 to up-regulate the expression of HDAC7, which protects against HIBD in neonatal rats.
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Project description:IntroductionCervical cancer is the second most common type of cancer and the third leading cause of cancer deaths in females in developing countries. Recent studies showed that long non-coding RNAs play a key role in human cancers. However, the molecular mechanisms underlying the initiation and progression of cervical cancer remained to be further explored.Material and methodsIn this study, we explored the differential expression of lncRNAs and mRNAs in cervical cancer progression by analyzing the public dataset GSE63514. Next, PPI and co-expression networks were constructed to reveal the potential roles of cervical cancer related mRNAs and lncRNAs. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to explore functions of differentially expressed genes (DEGs) in cervical cancer.ResultsIn the present study, we observed that 3021 mRNAs were up-regulated and 1605 mRNAs were down-regulated in cervical cancer progression. Meanwhile, we for the first time found that 172 lncRNAs were up-regulated and 106 lncRNAs were down-regulated in cervical cancer progression. Co-expression network analysis showed that lncRNAs were widely co-expressed with cell cycle related genes in cervical cancer, implicating the important roles of these lncRNAs in cell proliferation regulation. Of note, we identified two hub lncRNA-mRNA networks involved in regulating various biological processes in cervical cancer progression.ConclusionsOur results identified key mRNAs and lncRNAs in cervical cancer progression. This study will provide novel insights to explore the potential mechanisms underlying cervical cancer progression.
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