scholarly journals Coding and non-coding RNA dysregulation in bipolar disorder

2018 ◽  
Author(s):  
Jurjen J. Luykx ◽  
F. Giuliani ◽  
G. Giuliani ◽  
J.H. Veldink
Keyword(s):  
Bipolar Disorder ◽  
Alternative Splicing ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Differentially Expressed ◽  
Postmortem Brain ◽  
Healthy Controls ◽  
Non Coding Rna ◽  
Postmortem Brain Tissue ◽  
Alternative Splicing Events

AbstractThe molecular mechanisms underlying bipolar disorder (BPD) have remained largely unknown. Postmortem brain tissue studies comparing BPD patients with healthy controls have produced a heterogeneous array of potentially implicated protein-coding RNAs. We hypothesized that dysregulation of not only coding, but multiple classes of RNA (coding RNA, long non-coding (lnc) RNA, circular (circ) RNA, and/or alternative splicing) underlie the pathogenesis of BPD. Using non-polyadenylated libraries we performed RNA sequencing in postmortem human medial frontal gyrus tissue from BPD patients and healthy controls. We found twenty genes, some of which not previously implicated in BPD, differentially expressed. PCR validation and replication confirmed the implication of these DE genes. Functional analyses identified enrichment of angiogenesis, vascular system development and histone H3-K4 demethylation. In addition, ten lncRNA transcripts were differentially expressed. Furthermore, we detected an overall increased number of alternative splicing events in BPD, as well as an increase in the number of genes carrying alternative splicing events. Finally, we report altered levels of two circular transcripts, cNEBL and cEPHA3. In conclusion, our non-coding RNA findings demonstrate that RNA dysregulation in BPD is not limited to coding regions, opening avenues for future pharmacological investigations and biomarker research.

scholarly journals Coding and Non-Coding RNA Abnormalities in Bipolar Disorder

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 946 ◽  
Author(s):  
Luykx ◽  
Giuliani ◽  
Giuliani ◽  
Veldink
Keyword(s):  
Bipolar Disorder ◽  
Alternative Splicing ◽  
Brain Tissue ◽  
Molecular Mechanisms ◽  
Differentially Expressed ◽  
Healthy Controls ◽  
Large Reservoir ◽  
Non Coding Rna ◽  
Postmortem Brain Tissue ◽  
Alternative Splicing Events

The molecular mechanisms underlying bipolar disorder (BPD) have remained largely unknown. Postmortem brain tissue studies comparing BPD patients with healthy controls have produced a heterogeneous array of potentially implicated protein-coding RNAs. We hypothesized that dysregulation of not only coding, but multiple classes of RNA (coding RNA, long non-coding (lnc) RNA, circular (circ) RNA, and/or alternative splicing) underlie the pathogenesis of BPD. Using non-polyadenylated libraries we performed RNA sequencing in postmortem human medial frontal gyrus tissue from BPD patients and healthy controls. Twenty genes, some of which not previously implicated in BPD, were differentially expressed (DE). PCR validation and replication confirmed the implication of these DE genes. Functional in silico analyses identified enrichment of angiogenesis, vascular system development and histone H3-K4 demethylation. In addition, ten lncRNA transcripts were differentially expressed. Furthermore, an overall increased number of alternative splicing events in BPD was detected, as well as an increase in the number of genes carrying alternative splicing events. Finally, a large reservoir of circRNAs populating brain tissue not affected by BPD is described, while in BPD altered levels of two circular transcripts, cNEBL and cEPHA3, are reported. cEPHA3, hitherto unlinked to BPD, is implicated in developmental processes in the central nervous system. Although we did not perform replication analyses of non-coding RNA findings, our findings hint that RNA dysregulation in BPD is not limited to coding regions, opening avenues for future pharmacological investigations and biomarker research.

Deregulated microRNA expression in biospecimens from patients diagnosed with schizophrenia and bipolar disorder as a disease biomarker

2014 ◽  
Vol 5 (3) ◽  
Author(s):  
Ivana Delalle ◽  
Patricia Kao ◽  
Jason Choi
Keyword(s):  
Bipolar Disorder ◽  
Postmortem Brain ◽  
Treatment Efficiency ◽  
Rna Molecules ◽  
Non Coding Rna ◽  
Postmortem Brain Tissue ◽  
Neuropsychiatric Diseases ◽  
Molecular Machinery ◽  
Cell Processes ◽  
The Central Nervous System

AbstractThe biological markers for schizophrenia (SZ) and bipolar disorder (BD) would represent a precious tool in evaluating the risk for the development of these common neuropsychiatric diseases and, possibly, in the prevention of either disease episodes and/or treatment efficiency monitoring. Since both SZ and BD are diseases with a significant genetic component, the research over the last decades has focused on the genes with altered function in the central nervous system (CNS) of individuals suffering from these illnesses. Recently, however, small non-coding RNA molecules (microRNAs, miRNAs, miRs) were shown to regulate the expression of human CNS genes involved in cell processes and functions negatively affected in neuropsychiatric disorders, including synaptic development and maturation, learning and memory. Differentially expressed sets of miRNAs have been reported in the tissues of SZ and BD patients in comparison to controls suggesting the emergence of a novel class of potential biomarkers. Here we review the reports on the changes in miRNA expression in postmortem brain tissue and peripheral blood in SZ and BD. We also evaluate the potential of miRNA packaged in exosomes, signaling vesicles released by neurons and glia, to contribute to the disaggregation of the molecular machinery underlying mental disorders and provide clinically useful biomarkers.

RNA Sequencing in Bipolar Disorder: From Long Non-coding to Circular rnas

2017 ◽  
Vol 41 (S1) ◽  
pp. S56-S56 ◽  
Author(s):  
J. Luykx ◽  
F. Giuliani ◽  
J. Veldink ◽  
R. Kahn
Keyword(s):  
Bipolar Disorder ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Wide Spectrum ◽  
Postmortem Brain ◽  
Circular Rnas ◽  
Large Reservoir ◽  
Protein Coding ◽  
Medial Frontal Gyrus

Bipolar disorder (BPD) is a highly debilitating psychiatric disorder. The underlying molecular mechanisms of BPD remain largely unknown. Studies targeting postmortem brain tissues of BPD patients have identified very few consistently replicated differences in the expression levels of protein-coding RNAs across different areas of the brain. Since differential expression of the human genome produces a wide spectrum of protein-coding and noncoding RNAs, we hypothesized that major molecular deficits associated with BPD could reflect dysregulation of multiple classes of RNA. To test this hypothesis, we obtained postmortem human medial frontal gyrus tissue from BPD patients and healthy controls (n = 16). To survey the implication of both protein-coding and long non-coding RNAs (lncRNAs) in BPD, we then performed RNA sequencing, PCR validation and replication experiments adopting a case-control design. Thirty-six genes and fifteen lncRNA transcripts not previously implicated in BPD were detected as differentially expressed (FDR < 0.1). Functional analyses identified enrichments of angiogenesis, vascular system development and histone H3-K4 demethylation. In addition, we report extensive alternative splicing defects in the brains of BPD subjects compared to controls. Finally, we describe for the first time a large reservoir of circular RNAs (circRNAs) that populate the medial frontal gyrus and report significantly altered levels of two circular transcripts (cNEBL and cEPHA3) from the NEBL and EPHA3 loci in BPD. Our findings may not only contribute to gain insight into the pathophysiology of BPD but may be tested in the near future as potential biomarkers for diagnostics.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Drugs used to treat bipolar disorder act via microRNAs to regulate expression of genes involved in neurite outgrowth

2020 ◽  
Vol 34 (3) ◽  
pp. 370-379 ◽  
Author(s):  
Srisaiyini Kidnapillai ◽  
Ben Wade ◽  
Chiara C Bortolasci ◽  
Bruna Panizzutti ◽  
Briana Spolding ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Neurite Outgrowth ◽  
Neural Plasticity ◽  
Drug Combination ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Drug Effects ◽  
Differentially Expressed ◽  
Transcriptional Level ◽  
Expression Of Genes

Background: The drugs commonly used to treat bipolar disorder have limited efficacy and drug discovery is hampered by the paucity of knowledge of the pathophysiology of this disease. This study aims to explore the role of microRNAs in bipolar disorder and understand the molecular mechanisms of action of commonly used bipolar disorder drugs. Methods: The transcriptional effects of bipolar disorder drug combination (lithium, valproate, lamotrigine and quetiapine) in cultured human neuronal cells were studied using next generation sequencing. Differential expression of genes ( n=20) and microRNAs ( n=6) was assessed and the differentially expressed microRNAs were confirmed with TaqMan MicroRNA Assays. The expression of the differentially expressed microRNAs were inhibited to determine bipolar disorder drug effects on their target genes ( n=8). Independent samples t-test was used for normally distributed data and Kruskal-Wallis/Mann-Whitney U test was used for data not distributed normally. Significance levels were set at p<0.05. Results: We found that bipolar disorder drugs tended to increase the expression of miR-128 and miR-378 ( p<0.05). Putative target genes of these microRNAs targeted pathways including those identified as “neuron projection development” and “axonogenesis”. Many of the target genes are inhibitors of neurite outgrowth and neurogenesis and were downregulated following bipolar disorder drug combination treatment (all p<0.05). The bipolar disorder drug combination tended to decrease the expression of the target genes ( NOVA1, GRIN3A, and VIM), however this effect could be reversed by the application of microRNA inhibitors. Conclusions: We conclude that at a transcriptional level, bipolar disorder drugs affect several genes in concert that would increase neurite outgrowth and neurogenesis and hence neural plasticity, and that this effect is mediated (at least in part) by modulation of the expression of these two key microRNAs.

scholarly journals Alternative splicing of leptin receptor overlapping transcript in osteosarcoma

2020 ◽  
Vol 245 (16) ◽  
pp. 1437-1443
Author(s):  
Emel Rothzerg ◽  
Xuan D Ho ◽  
Jiake Xu ◽  
David Wood ◽  
Aare Märtson ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Molecular Mechanisms ◽  
Leptin Receptor ◽  
Osteogenic Sarcoma ◽  
Differentially Expressed ◽  
Primary Malignancy ◽  
Transcript Variants ◽  
Potential Biomarker ◽  
Whole Transcriptome Analysis ◽  
Tumor Biopsies

Alternative splicing of RNA is an essential mechanism that increases proteomic diversity in eukaryotic cells. Aberrant alternative splicing is often associated with various human diseases, including cancer. We conducted whole-transcriptome analysis of 18 osteosarcoma bone samples (paired normal—tumor biopsies). Using RNA-seq, we identified statistically significant (FDR <0.05) 26 differentially expressed transcript variants of leptin receptor overlapping transcript ( LEPROT) gene. Some of the transcripts were overexpressed in normal cells, whereas others were overexpressed in tumor cells. The function of LEPROT is not completely understood. Herein, we highlight a possible association between OS and aberrant alternative splicing events and its interaction with the expression of LEPROT. We also discuss the role of LEPROT in regulating growth hormone and its receptor, and the relationship with initiation and progression of OS. This research study may help to understand the association of alternative splicing mechanism in OS and in tumorigenesis more generally. Further, LEPROT gene can also be considered as a potential biomarker of osteosarcoma. Impact statement Osteosarcoma (OS, also known as osteogenic sarcoma) is the most common primary malignancy of bone in children and adolescents. The molecular mechanisms of OS are extremely complicated and its molecular mediators remain to be elucidated. We sequenced total RNA from 18 OS bone samples (paired normal—tumor biopsies). We found statistically significant (FDR <0.05) 26 differentially expressed transcript variants of LEPROT gene with different expressions in normal and tumor samples. These findings contribute to the understanding of molecular mechanisms of OS development and provide encouragement to pursue further research.

scholarly journals Identification of Differentially Expressed Proteins in Sugarcane in Response to Infection by Xanthomonas albilineans Using iTRAQ Quantitative Proteomics

2020 ◽  
Vol 8 (1) ◽  
pp. 76
Author(s):  
Jian-Yu Meng ◽  
Mbuya Sylvain Ntambo ◽  
Philippe C. Rott ◽  
Hua-Ying Fu ◽  
Mei-Ting Huang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Vascular System ◽  
Lipid Transfer Protein ◽  
Differentially Expressed ◽  
Post Inoculation ◽  
Differentially Expressed Proteins ◽  
Lipid Transfer ◽  
Leaf Scald ◽  
Improvement Programs ◽  
Xanthomonas Albilineans

Sugarcane can suffer severe yield losses when affected by leaf scald, a disease caused by Xanthomonas albilineans. This bacterial pathogen colonizes the vascular system of sugarcane, which can result in reduced plant growth and plant death. In order to better understand the molecular mechanisms involved in the resistance of sugarcane to leaf scald, a comparative proteomic study was performed with two sugarcane cultivars inoculated with X. albilineans: one resistant (LCP 85-384) and one susceptible (ROC20) to leaf scald. The iTRAQ (isobaric tags for relative and absolute quantification) approach at 0 and 48 h post-inoculation (hpi) was used to identify and annotate differentially expressed proteins (DEPs). A total of 4295 proteins were associated with 1099 gene ontology (GO) terms by GO analysis. Among those, 285 were DEPs during X. albilineans infection in cultivars LCP 85-384 and ROC20. One hundred seventy-two DEPs were identified in resistant cultivar LCP 85-384, and 113 of these proteins were upregulated and 59 were downregulated. One hundred ninety-two DEPs were found in susceptible cultivar ROC20 and half of these (92) were upregulated, whereas the other half corresponded to downregulated proteins. The significantly upregulated DEPs in LCP 85-384 were involved in metabolic pathways, the biosynthesis of secondary metabolites, and the phenylpropanoid biosynthesis pathway. Additionally, the expression of seven candidate genes related to photosynthesis and glycolytic pathways, plant innate immune system, glycosylation process, plant cytochrome P450, and non-specific lipid transfer protein was verified based on transcription levels in sugarcane during infection by X. albilineans. Our findings shed new light on the differential expression of proteins in sugarcane cultivars in response to infection by X. albilineans. The identification of these genes provides important information for sugarcane variety improvement programs using molecular breeding strategies.

scholarly journals Identification of Non-coding RNA Biomarkers in Stress-induced Depression via Comprehensive Analysis of Competing Endogenous RNA Network

2020 ◽  
Author(s):  
xuanjun liu ◽  
Lan Yan ◽  
Chun Lin ◽  
Yiliang Zhang ◽  
Haofei Miao ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Comprehensive Analysis ◽  
Differentially Expressed ◽  
Psychiatric Disease ◽  
Circular Rnas ◽  
Messenger Rnas ◽  
Competing Endogenous Rna ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Promising Perspective

Abstract BackgroundDepression is one of the most common psychiatric disease worldwide. Although the research about the pathogenesis of depression have achieved progress, the detailed effect of non-coding RNAs (ncRNAs) in depression are still not clearly elucidated. This study was aimed to identify non-coding RNA biomarkers in stress-induced depression via comprehensive analysis of competing endogenous RNA networkMethodsIn this present study, we acquired RNA expression from RNA seq expression profile in three mice with depressive-like behaviors using chronic restraint stress paradigm and three C57BL/6J wild-type mice as control mice. ResultsA total of 41 differentially expressed circular RNAs (circRNAs) and 181 differentially expressed messenger RNAs (mRNAs) were up-regulated, and 65 differentially expressed circRNAs and 289 differentially expressed mRNAs were down-regulated, which were selected by a threshold of fold change ≥2 and a p-value < 0.05. Gene Ontology was performed to analyze the biological functions, and we predicted potential signaling pathways based on Kyoto Encyclopedia of Genes and Genomes pathway database. In addition, we constructed a circRNA-microRNA (miRNA)-mRNA regulatory network to further identify non-coding RNAs biomarkers. ConclusionsOur findings provide a promising perspective for further research into molecular mechanisms of depression, and targeting circRNA -mediated competing endogenous RNA (ceRNA) network is a useful strategy to early recognize the depression.

scholarly journals PO-046 Gene expression profiling of peripheral blood mononuclear cells in young male trampoline athletes

2018 ◽  
Vol 1 (3) ◽  
Author(s):  
Li Gao ◽  
Yong Jie Yang ◽  
En Qi Li ◽  
Jia Ning Mao
Keyword(s):  
Gene Expression ◽  
Differentially Expressed Genes ◽  
Bone Health ◽  
Expression Profiling ◽  
Molecular Mechanisms ◽  
Interaction Network ◽  
Differentially Expressed ◽  
Signal Pathways ◽  
Healthy Controls ◽  
Mineral Density

Objective Evidence indicates that physical activity influence bone health. However, the molecular mechanisms mediating the beneficial adaptations to exercise are not well understood. The purpose of this study was to examine the differentially expressed genes in PBMC between athletes and healthy controls, and to analyze the important functional genes and signal pathways that cause increased bone mineral density in athletes, in order to further reveal the molecular mechanisms of exercise promoting bone health. Methods Five professional trampoline athletes and five age-matched untrained college students participated in this study. Used the human expression Microarray V4.0 expression profiling chip to detect differentially expressed genes in the two groups, and performed KEGG Pathway analysis and application of STRING database to construct protein interaction Network; Real-Time PCR technology was used to verify the expression of some differential genes.  Results Compared with healthy controls, there were significant improvement in lumbar spine bone mineral density, and 236 up-regulated as well as 265 down-regulated in serum samples of athletes. The differentially expressed genes involved 28 signal pathways, such as cell adhesion molecules. Protein interaction network showed that MYC was at the core node position. Real-time PCR results showed that the expression levels of CD40 and ITGα6 genes in the athletes were up-regulated compared with the healthy controls, the detection results were consistent with that of the gene chip. Conclusions The findings highlight that long-term high-intensity trampoline training could induce transcriptional changes in PBMC of the athletes. These data suggest that gene expression fingerprints can serve as a powerful research tool to design novel strategies for monitoring exercise. The findings of the study also provide support for the notion that PBMC could be used as a substitute to study exercise training that affects bone health.

Exploring the Potential Pathogenic Mechanisms of Asthma Deterioration Based on Modular Drivers

2021 ◽  
Vol 7 (4) ◽  
pp. 756-764
Author(s):  
Jianhua Liu ◽  
Liqing Zheng ◽  
Liang Cao ◽  
Changhong Zhang ◽  
Chen Li
Keyword(s):  
Cellular Response ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Hypergeometric Test ◽  
Asthmatic Patients ◽  
Pathogenic Genes ◽  
Non Coding Rna ◽  
Asthma Patients ◽  
Differential Genes

Asthma is a complicated chronic airway inflammatory disease caused by the interaction of genetic susceptibility and environmental impact. Although biologists have explored the pathogenesis of asthma in various aspects, the exact molecular mechanism continues to be elusive. In this study, we conducted a modular study of asthma-related genes to explore their core pathogenic driving genes. Firstly, the expression profiles of normal, mild to moderate and severe asthma patients were analyzed to screen the differentially expressed genes. Secondly, differential genes of asthma were integrated, co-expressed and clustered into modules. Next, enrichment of GO function and KEGG pathway of module genes were analyzed. Finally, non-coding RNA (ncRNA) and transcription factors that regulate modules are predicted by hypergeometric test. In summary, we have obtained 14 co-expression modules, among which CDCA5, JUNB and other genes are significantly differentially expressed in asthmatic patients, and have an active regulatory role in dysfunction module, so they are recognized as asthma-driving genes. Enrichment results showed that module genes were significantly involved in cell growth, transcription factor activity, cellular response to drugs and the transport of various ions. In addition, they also radically regulate Wnt, TGF-beta, JAK-STAT and extracellular matrix signaling pathways. Finally, we identified significant regulatory dysfunction modules of ncRNA pivot (including miR-181a-5p and let-7d-5p) and TF pivot (including NFKB1, ESR1 and MYC). Overall, our work has uncovered a co-expression network involved in the regulation of core pathogenic genes of asthma. It helps to reveal the core dysfunction modules and potential regulatory factors of this disease, and to enhance our understanding of the molecular mechanisms of asthma-related diseases.

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