Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Human colon expression in healthy, CD, treated CD, and UC

ABSTRACT: Activation of inflammatory pathways in human IBD IL-6:STAT3 pathways are activated in the affected colon in IBD. However, the functional implications of this are not known. We hypothesized that pro-inflammatory IL-6:STAT3 dependent networks would be up regulated in the colon of pediatric patients with Crohn Disease (CD) and Ulcerative Colitis (UC), and that these would regulate leukocyte survival, proliferation, and recruitment to the gut. These experiments tested differential colon gene expression relative to these pathways in healthy, CD, and UC samples. Colon biopsy samples were obtained from CD and UC patients at diagnosis, CD patients during therapy, and healthy controls. The global pattern of gene expression was determined using GeneSpring software, and biological networks were identified using Ingenuity software. Data suggested that two IL-6:STAT3 dependent networks are up regulated in pediatric IBD both at diagnosis and during therapy which regulate leukocyte recruitment and survival. The degree of up regulation of these genes compared to healthy controls was remarkably conserved across the two CD groups and the UC groups, suggesting common mechanisms of mucosal inflammation. Colon RNA was isolated from biopsies obtained from CD at diagnosis and during therapy, UC at diagnosis, and healthy controls. Samples were obtained from the most proximal affected segment of colon. Microarray experiments were performed as described in the CCHMC microarray core, and data was analyzed as described above in the summary. The '107' internal control CEL files (for batches 1-4) used for normalization of the Sample VALUEs are linked below as supplementary files.

ORGANISM(S): Homo sapiens

SUBMITTER: Lee Denson

PROVIDER: E-GEOD-9686 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Activation of an IL-6:STAT3-dependent transcriptome in pediatric-onset inflammatory bowel disease.

Carey Rebecca R Jurickova Ingrid I Ballard Edgar E Bonkowski Erin E Han Xiaonan X Xu Huan H Denson Lee A LA

Inflammatory bowel diseases 20080401 4

<h4>Background</h4>While activation of the IL-6-dependent transcription factor signal transducer and activator of transcription 3 (STAT3) has been implicated in the pathogenesis of inflammatory bowel disease (IBD), a direct effect on mucosal gene expression and inflammation has not been shown. We hypothesized that a proinflammatory IL-6:STAT3-dependent biological network would be up regulated in pediatric-onset IBD patients, and would be associated with the severity of mucosal inflammation.<h4>M ...[more]

PMID: 18069684

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Project description:Inflammatory bowel disease (IBD) patients are generally at an increased risk for viral diseases. Viral infections of tissue affected by chronic IBD are insufficiently understood, especially in the context of flare-ups; while some studies have confidently shown aggravation of symptoms in large cohorts, others found no association. Although not considered at an increased risk of Coronavirus Disease 2019 (COVID-19), IBD patients suffer more frequent gastrointestinal symptoms during COVID-19 and a worse outcome has been associated with certain IBD medications and disease activity. For this reason, we generated intestinal epithelial organoids from ileum with Crohn’s disease (CD) and colon with ulcerative colitis (UC) together with healthy controls. Each group included five to six patients. Using RNA sequencing we showed that IBD organoids were not more susceptible to infection. The highest viral load two days after infection was in healthy ileum and is correlated to the expression of SARS-CoV-2 entry receptor ACE2 and proteases CTSL/B. Pathway analyses determined an apparently weaker defense reaction in CD organoids to SARS-CoV-2 which could simply be due to the lower viral load compared to the healthy group. In contrast to CD, there was an activation of viral defense in infected UC colon, especially interferon signaling, resembling highly infected healthy ileum. This was not seen in healthy colon and was unexpected since UC and healthy colon did not differ in viral load. In uninfected IBD organoids compared to healthy, there was an already stronger basal expression of genes implicated in viral defense, for example, of viral sensors OAS1 and OASL in CD and interferon regulatory transcription factor IRF7 in UC. Some were further influenced by SARS-CoV-2 infection with notable differences between CD and UC. To conclude, infection with SARS-CoV-2 did not lead to higher viral numbers in IBD organoids providing reassurance for patients in remission. Still, we observed a more pronounced epithelial defense reaction to the virus in UC colon, prompting further investigations on whether this could be the reason for stronger gastrointestinal symptoms of COVID-19 seen in IBD patients or if it could lead to a consequent IBD flare.

Project description:Inflammatory bowel disease (IBD) is a complex multi-factorial inflammatory disease with Crohn’s disease (CD) and ulcerative colitis (UC) being the two most common forms. A number of transcriptional profiling studies have provided compelling evidence that describe the role of protein-coding genes and microRNAs in modulating the immune responses in IBD. In the present study, we performed a genome-wide transcriptome profiling of lncRNAs and protein-coding genes in inflamed and non-inflamed colon pinch biopsies from the IBD patients using expression microarrays platform. In this study, we identified widespread dysregulation of lncRNAs and protein-coding genes in both inflamed and non-inflamed CD and UC compared to the healthy controls. In case of inflamed CD and UC (iCD and iUC), we identified 438 and 745 differentially expressed lncRNAs, respectively, while in case of the non-inflamed CD and UC (niCD and niUC), we identified 12 and 19 differentially expressed lncRNAs, respectively. We also observed significant enrichment (p-value < 0.001, Pearson’s Chi-squared test) for 96 differentially expressed lncRNAs and 154 protein-coding genes within the IBD susceptibility loci. Furthermore, we found strong positive expression correlations for the intersecting and cis-neighboring differentially expressed IBD loci-associated lncRNA-protein-coding gene pairs. The functional annotation analysis of differentially expressed genes revealed that they are involved in immune response, pro-inflammatory cytokine activity and MHC protein complex. The lncRNA expression profiling in both inflamed and non-inflamed CD and UC, successfully stratified IBD patients from the healthy controls. Taken together, the identified lncRNA transcriptional signature along with clinically relevant parameters suggests their potential as biomarkers in IBD. A total of 96 biopsy samples (including 6 samples used as technical replicates) extracted from different colonic locations from 45 patients (CD=13, UC=20, Controls=12) were profiled using Agilent Custom 8x60K format lncRNA expression microarray. In Gencode v15 lncRNA microarray design, each lncRNA transcript is targeted by two probes covering 22,001 lncRNA transcripts corresponding to 12,963 lncRNA genes. In addition, each array contains 17,535 randomly-selected protein-coding targets, of which 15,182 (unique 12,787) correspond to protein-coding genes.

Dataset Information

Human colon expression in healthy, CD, treated CD, and UC

Publications

Activation of an IL-6:STAT3-dependent transcriptome in pediatric-onset inflammatory bowel disease.

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