scholarly journals A long noncoding RNA signature for ulcerative colitis identifies IFNG-AS1 as an enhancer of inflammation

2016 ◽  
Vol 311 (3) ◽  
pp. G446-G457 ◽  
Author(s):  
David Padua ◽  
Swapna Mahurkar-Joshi ◽  
Ivy Ka Man Law ◽  
Christos Polytarchou ◽  
John P. Vu ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
T Cells ◽  
Noncoding Rna ◽  
Inflammatory Cytokine ◽  
Inflammatory Responses ◽  
Cell Model ◽  
Differentially Expressed ◽  
P Value ◽  
Susceptibility Loci ◽  
And Control

High-throughput technologies revealed new categories of genes, including the long noncoding RNAs (lncRNAs), involved in the pathogenesis of human disease; however, the role of lncRNAs in the ulcerative colitis (UC) has not been evaluated. Gene expression profiling was used to develop lncRNA signatures in UC samples. Jurkat T cells were activated by PMA/ionomycin subsequently interferon-γ (IFNG) and tumor necrosis factor (TNF)-α protein levels were assessed by ELISA. Anti-sense molecules were designed to block IFNG-AS1 expression. A unique set of lncRNAs was differentially expressed between UC and control samples. Of these, IFNG-AS1 was among the highest statistically significant lncRNAs (fold change: 5.27, P value: 7.07E−06). Bioinformatic analysis showed that IFNG-AS1 was associated with the IBD susceptibility loci SNP rs7134599 and its genomic location is adjacent to the inflammatory cytokine IFNG. In mouse models of colitis, active colitis samples had increased colonic expression of this lncRNA. Utilizing the Jurkat T cell model, we found IFNG-AS1 to positively regulate IFNG expression. Novel lncRNA signatures differentiate UC patients with active disease, patients in remission, and control subjects. A subset of these lncRNAs was found to be associated with the clinically validated IBD susceptibility loci. IFNG-AS1 was one of these differentially expressed lncRNAs in UC patients and found to regulate the key inflammatory cytokine, IFNG, in CD4 T cells. Taking these findings together, our study revealed novel lncRNA signatures deregulated in UC and identified IFNG-AS1 as a novel regulator of IFNG inflammatory responses, suggesting the potential importance of noncoding RNA mechanisms on regulation of inflammatory bowel disease-related inflammatory responses.

scholarly journals Global Long Noncoding RNA and mRNA Expression Changes between Prenatal and Neonatal Lung Tissue in Pigs

Genes ◽  
2018 ◽  
Vol 9 (9) ◽  
pp. 443 ◽  
Author(s):  
Long Jin ◽  
Silu Hu ◽  
Teng Tu ◽  
Zhiqing Huang ◽  
Qianzi Tang ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Proliferation ◽  
Lung Tissue ◽  
Long Noncoding Rna ◽  
Lung Development ◽  
Noncoding Rna ◽  
Differentially Expressed ◽  
P Value ◽  
Distal Lung ◽  
Neonatal Lungs

Lung tissue plays an important role in the respiratory system of mammals after birth. Early lung development includes six key stages, of which the saccular stage spans the pre- and neonatal periods and prepares the distal lung for alveolarization and gas-exchange. However, little is known about the changes in gene expression between fetal and neonatal lungs. In this study, we performed transcriptomic analysis of messenger RNA (mRNA) and long noncoding RNA (lncRNA) expressed in the lung tissue of fetal and neonatal piglets. A total of 19,310 lncRNAs and 14,579 mRNAs were identified and substantially expressed. Furthermore, 3248 mRNAs were significantly (FDR-adjusted p value ≤ 0.05, FDR: False Discovery Rate) differentially expressed and were mainly enriched in categories related to cell proliferation, immune response, hypoxia response, and mitochondrial activation. For example, CCNA2, an important gene involved in the cell cycle and DNA replication, was upregulated in neonatal lungs. We also identified 452 significantly (FDR-adjusted p value ≤ 0.05) differentially expressed lncRNAs, which might function in cell proliferation, mitochondrial activation, and immune response, similar to the differentially expressed mRNAs. These results suggest that differentially expressed mRNAs and lncRNAs might co-regulate lung development in early postnatal pigs. Notably, the TU64359 lncRNA might promote distal lung development by up-regulating the heparin-binding epidermal growth factor-like (HB-EGF) expression. Our research provides basic lung development datasets and will accelerate clinical researches of newborn lung diseases with pig models.

scholarly journals Construction and Comprehensive Analysis of Dysregulated Long Noncoding RNA-Associated Competing Endogenous RNA Network in Moyamoya Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xuefeng Gu ◽  
Dongyang Jiang ◽  
Yue Yang ◽  
Peng Zhang ◽  
Guoqing Wan ◽  
...  
Keyword(s):  
Moyamoya Disease ◽  
Cerebral Artery ◽  
Regulatory Network ◽  
Noncoding Rna ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Competing Endogenous Rna ◽  
Cerna Network ◽  
And Control ◽  
Control Samples

Background. Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by chronic progressive stenosis or occlusion of the bilateral internal carotid artery (ICA), the anterior cerebral artery (ACA), and the middle cerebral artery (MCA). MMD is secondary to the formation of an abnormal vascular network at the base of the skull. However, the etiology and pathogenesis of MMD remain poorly understood. Methods. A competing endogenous RNA (ceRNA) network was constructed by analyzing sample-matched messenger RNA (mRNA), long non-coding RNA (lncRNA), and microRNA (miRNA) expression profiles from MMD patients and control samples. Then, a protein-protein interaction (PPI) network was constructed to identify crucial genes associated with MMD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were employed with the DAVID database to investigate the underlying functions of differentially expressed mRNAs (DEmRNAs) involved in the ceRNA network. CMap was used to identify potential small drug molecules. Results. A total of 94 miRNAs, 3649 lncRNAs, and 2294 mRNAs were differentially expressed between MMD patients and control samples. A synergistic ceRNA lncRNA-miRNA-mRNA regulatory network was constructed. Core regulatory miRNAs (miR-107 and miR-423-5p) and key mRNAs (STAT5B, FOSL2, CEBPB, and CXCL16) involved in the ceRNA network were identified. GO and KEGG analyses indicated that the DEmRNAs were involved in the regulation of the immune system and inflammation in MMD. Finally, two potential small molecule drugs, CAY-10415 and indirubin, were identified by CMap as candidate drugs for treating MMD. Conclusions. The present study used bioinformatics analysis of candidate RNAs to identify a series of clearly altered miRNAs, lncRNAs, and mRNAs involved in MMD. Furthermore, a ceRNA lncRNA-miRNA-mRNA regulatory network was constructed, which provides insights into the novel molecular pathogenesis of MMD, thus giving promising clues for clinical therapy.

scholarly journals Identification of Differentially Expressed lncRNAs in a CpG ODN-Activated Macrophage

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Ying Zheng ◽  
Xi Luo ◽  
Zailong Qin ◽  
Zhiguang Zhou
Keyword(s):  
Noncoding Rna ◽  
Inflammatory Responses ◽  
Differentially Expressed ◽  
Cpg Odn ◽  
Protein Coding ◽  
Cpg Dna ◽  
Time Points ◽  
Pathway Analyses ◽  
Coexpression Networks ◽  
Coding Capacity

A macrophage is an important component of innate immunity which can be activated by infection. A series of inflammatory cytokines are produced and released to eliminate pathogens. CpG DNA is an immune stimulator recognized by TLR9, subsequently inducing inflammatory responses in macrophages. Long noncoding RNA (lncRNA) is a novel class of noncoding RNA, whose length is more than 200 nt, but without protein-coding capacity. lncRNAs are involved in many physiological and pathological processes, including inflammatory responses. In our study, a lncRNA microarray assay was performed to identify differentially expressed lncRNAs and mRNAs in RAW264.7 cells at different time points following CpG ODN stimulation. The results revealed that expression levels of 734 lncRNAs and 734 mRNAs were altered at all time points. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analyses were performed to predict the functions of dysregulated genes. Coexpression networks of lncRNA-mRNA were constructed based on the correlation analysis between differentially expressed lncRNAs and 10 selected upregulated mRNAs, which have been reported to be involved in CpG DNA-induced inflammatory responses. In addition, we selected 8 dysregulated lncRNAs for further validation by quantitative real-time PCR. The present study provided a systematic perspective on the potential functions of lncRNAs in CpG ODN-induced macrophage activation.

Gene Expression Profiles of CD34+ Cells from PBSC Grafts Predict for Development of t-MDS Following Autologous Transplantation for HL/NHL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2433-2433
Author(s):  
Liang Li ◽  
Xiwei Wu ◽  
David Smith ◽  
Jerald P. Radich ◽  
Lue Ping Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Error Rate ◽  
Prediction Error ◽  
Expression Profiles ◽  
Null Distribution ◽  
Gene Expression Profiles ◽  
Error Rates ◽  
Differentially Expressed ◽  
P Value ◽  
And Control

Abstract Therapy-related myelodysplasia (t-MDS) is a lethal complication of autologous hematopoietic cell transplant (HCT) for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). The development of t-MDS after HCT appears related to pre-HCT genotoxic exposures. Here we investigated whether alterations in gene expression patterns in hematopoietic stem cells (HSC) from peripheral blood stem cell (PBSC) autografts was associated with subsequent development of t-MDS after HCT. We analyzed pre-HCT PBSC samples from 18 patients who developed t-MDS and 38 controls (matched for primary diagnosis, age at HCT, race/ ethnicity, and length of follow-up) that did not develop t-MDS after HCT for HL/NHL. CD34+ cells were selected using flow cytometry. RNA was extracted from 1000 cells, processed using the Affymetrix 2-Cycle Target labeling kit and hybridized on Affymetrix U133 Plus 2.0 microarrays. Following QC assessment, 16 t-MDS and 29 matched controls were selected for further analysis. Raw data were normalized using a RMA algorithm. 35042 transcripts were selected for analysis based on ≥4 arrays having intensity >16. Limma package was used to identify genes differentially expressed between t-MDS and control samples (FDR ≤ 0.01; and > 1.5-fold up or down-regulation) while controlling for matched groups. 877 differentially expressed transcripts representing 781 unique genes were identified. Of several classification algorithms tested, the K nearest neighbor (KNN) and Naïve Bayes (NB) were found to best predict t-MDS. To select the best genes for classification, a step forward method was used for prediction analysis. First, redundant transcripts were removed with only the most significant one of the redundant transcripts being kept and genes were ranked based on p-value. Prediction analyses were performed by starting with top 2 genes and incrementing one more gene at a time. Using this approach the top 5 genes best predicted the class labels using leave-one-out (LOO) cross validation with a prediction error of 22%. To determine the statistical significance of the prediction error rate, a permutation based approach was implemented to establish the null distribution of the error rate. This determines the probability of obtaining a cross-validated classification error as small as would be achieved if there were no difference between t-MDS and control. Sample labels were randomly permuted 10,000 times and cross-validated error rates were recalculated using LOO cross validation. Based on the null distribution of the permutated error rates, the original error rate (ER0=0.22) had a P value of 0.005, indicating that the likelihood of obtaining such a small prediction error for a cross-validated classifier by chance is very low. We are currently analyzing the differentially expressed genes to investigate for altered response to genotoxic stress and stem cell regulation in HSC from patients who subsequently develop t-MDS. In conclusion, we have shown that gene expression profiles of HSC from PBSC autografts from HL/NHL patients can differentiate patients who develop t-MDS after autologous HCT from those who do not develop t-MDS. The prediction power of these gene sets will be further verified using different sets of t-MDS case and control samples.

Inflammation and Inflammatory Cytokine Contribute to the Initiation and Development of Ulcerative Colitis and Its Associated Cancer

2019 ◽  
Vol 25 (10) ◽  
pp. 1595-1602 ◽  
Author(s):  
Dianbo Yao ◽  
Ming Dong ◽  
Chaoliu Dai ◽  
Shuodong Wu
Keyword(s):  
Ulcerative Colitis ◽  
Epithelial Cells ◽  
Inflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Intestinal Epithelial Cells ◽  
Bacterial Invasion ◽  
Intestinal Epithelial ◽  
Increased Risk

Abstract Dysregulated inflammatory responses play a pivotal role in the initiation, development, and progression of tumors, as demonstrated by the association between ulcerative colitis and the increased risk of colon carcinoma. In this review, the underlying mechanisms for the initiation and development of ulcerative colitis and colitis-associated cancer are described, mainly focusing on the inflammation and inflammatory cytokine. Disruption of the intestinal mucosal barrier and bacterial invasion resulted in intestinal inflammation; and further TLR4/NF-κB stimulation in intestinal epithelial cells, inflammatory cell infiltration, and inflammatory cytokine release all confer survival advantages to or promote abnormal proliferation in susceptible cells. Importantly, the respective roles of TLR4/NF-κB, TNF–α, and IL-6 in intestinal epithelial cells and inflammatory cells are summarized in detail. A thorough understanding of these molecular mechanisms may help researchers and clinicians to explore novel approaches for the prevention and treatment of colitis-associated cancer.

scholarly journals CD8+ T cell gene expression analysis identifies differentially expressed genes between multiple sclerosis patients and healthy controls

2020 ◽  
Vol 6 (4) ◽  
pp. 205521732097851
Author(s):  
IS Brorson ◽  
AM Eriksson ◽  
IS Leikfoss ◽  
V Vitelli ◽  
EG Celius ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Differential Gene Expression ◽  
Differentially Expressed Genes ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
P Value ◽  
Healthy Controls ◽  
Differential Gene ◽  
Multiple Sclerosis Patients

Background Genetic and clinical observations have indicated T cells are involved in MS pathology. There is little insight in how T cells are involved and whether or not these can be used as markers for MS. Objectives Analysis of the gene expression profiles of circulating CD8+ T cells of MS patients compared to healthy controls. Methods RNA from purified CD8+ T cells was sequenced and analyzed for differential gene expression. Pathway analyses of genes at several p-value cutoffs were performed to identify putative pathways involved. Results We identified 36 genes with significant differential gene expression in MS patients. Four genes reached at least 2-fold differences in expression. The majority of differentially expressed genes was higher expressed in MS patients. Genes associated to MS in GWAS showed enrichment amongst the differentially expressed genes. We did not identify enrichment of specific pathways amongst the differentially expressed genes in MS patients. Conclusions CD8+ T cells of MS patients show differential gene expression, with predominantly higher activity of genes in MS patients. We do not identify specific biological pathways in our study. More detailed analysis of CD8+ T cells and subtypes of these may increase understanding of how T cells are involved in MS.

scholarly journals P036 MicroRNA composition of colon crypt-top and crypt-bottom epithelial cells in Ulcerative Colitis

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S149-S149
Author(s):  
R Inčiūraitė ◽  
S Juzėnas ◽  
R Ramonaitė ◽  
J Skiecevičienė
Keyword(s):  
Ulcerative Colitis ◽  
Epithelial Cells ◽  
Expression Profile ◽  
Expression Profiles ◽  
Intestinal Barrier ◽  
Differentially Expressed ◽  
Small Rna Sequencing ◽  
P Value ◽  
Sequencing Data ◽  
Illumina Platform

Abstract Background Ulcerative colitis (UC) is a chronic relapsing large intestine condition of inflammatory origin1. One of the most common features of UC is the injury of the intestinal barrier, which is composed primarily of colonic epithelial cells (CEpCs)2. The aim of this study was to identify UC-induced miRNA markers in CEpCs by determining the miRNA expression profile changes in crypt-top and crypt-bottom CEpC populations during active (aUC) and inactive (iUC) UC. Methods Crypt-top and crypt-bottom CEpCs were sorted from biopsies of healthy control (HC) individuals (n=19), patients with aUC (n=17) and iUC (n=15) using FACS technology. Total RNA was extracted, small RNA sequencing libraries were prepared and sequenced using Illumina platform. Sequencing data was processed with nextflow-core/smrnaseq pipeline. Differential expression, correlation, miRNA-target interactions, gene set enrichment analyses and data visualisation were performed using Rstudio software packages DESeq2, isomiRs, multimiR, SingleCellExperiment, clusterProfiler, ReactomePA, etc. The miRNAs with an adjusted p-value < 0.05, and absolute value of log2 fold change > 1 were considered to be significantly differentially expressed. Results 432 unique miRNAs were identified in samples. Changes of expression profile during aUC were identified in crypt-bottom CEpCs (compared to: (i) HC - 23 miRNAs, (ii) iUC - 22 miRNAs), as well as in crypt-top CEpCs (compared to: (i) HC - 28 miRNAs, (ii) iUC - 9 miRNAs). Also, 7 miRNAs were differentially expressed in crypt-bottom CEpCs and 3 miRNAs in crypt-top CEpCs during iUC compared to HC. 5 miRNAs were identified to be differentially expressed during aUC, 2 miRNAs - during iUC, and 11 miRNAs in HC when comparing expression profiles of crypt-bottom and crypt-bottom CEpCs. We also identified 16 and 14 miRNAs which expression in crypt-bottom and crypt-top CEpCs moderately (0.5<rho<0.7) correlated with Mayo score, respectively. Finally, the gene sets of pathways revealed the involvement of several miRNAs in biological processes and molecular functions associated with UC pathogenesis. Conclusion The changes of expression profiles of miRNAs revealed that crypt-top and crypt-bottom CEpCs respond to inflammation differently, the expression of these miRNAs reflects disease activity and modulates the processes of UC pathogenesis. References

scholarly journals Identification of Different Proteins Binding to Na, K-ATPase α1 in LPS-Induced ARDS Cell Model by Proteomic Analysis

2022 ◽  
Author(s):  
Xu-Peng Wen ◽  
Guo Long ◽  
Yue-Zhong Zhang ◽  
He Huang ◽  
Tao-Hua Liu ◽  
...  
Keyword(s):  
Tight Junction ◽  
Cell Model ◽  
A549 Cells ◽  
Interaction Network ◽  
Differentially Expressed ◽  
Interacting Proteins ◽  
Differentially Expressed Proteins ◽  
Kegg Analysis ◽  
Proteomic Approach ◽  
And Control

Abstract Background: Acute respiratory distress syndrome (ARDS) is characterized by refractory hypoxemia caused by accumulation of pulmonary fluid, which is related to inflammatory cell infiltration, impaired tight junction of pulmonary epithelium and impaired Na, K-ATPase function, especially Na, K-ATPase α1 subunit. Up until now, the pathogenic mechanism at the level of protein during lipopolysaccharide- (LPS-) induced ARDS remains unclear.Methods: Using an unbiased, discovery and quantitative proteomic approach, we discovered the differentially expressed proteins binding to Na, K-ATPase α1 between LPS-A549 cells and Control-A549 cells. These Na, K-ATPase α1 interacting proteins were screened by co-immunoprecipitation (Co-IP) technology. Among them, some of the differentially expressed proteins with significant performance were identified and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The protein interaction network was constructed by the related Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Several differentially expressed proteins were validated by Western blot.Results: Of identified 1598 proteins, 89 were differentially expressed proteins between LPS-A549 cells and Control-A549 cells. Intriguingly, protein-protein interaction network showed that there were 244 significantly enriched co-expression among 60 proteins in the group control-A549. while the group LPS-A549 showed 43 significant enriched interactions among 29 proteins. The related GO and KEGG analysis found evident phenomena of ubiquitination and deubiquitination, as well as the pathways related to autophagy. Among proteins with rich abundance, there were several intriguing ones, including the deubiquitinase (OTUB1), the tight junction protein zonula occludens-1 (ZO-1), the scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complexes (CUL4B) and the autophagy-related protein sequestosome-1 (SQSTM1).Conclusions: In conclusion, our proteomic approach revealed targets related to the occurrence and development of ARDS, being the first study to investigate significant differences in Na, K-ATPase α1 interacting proteins between LPS-induced ARDS cell model and control-A549 cell. These proteins may help the clinical diagnosis and facilitate the personalized treatment of ARDS.

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