The emerging role of lncRNAs in inflammatory bowel disease.
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ABSTRACT:
SUBMITTER: Yarani R
PROVIDER: S-EPMC6283835 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
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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.
2015-04-10 | E-GEOD-67106 | biostudies-arrayexpress
Project description:The role of long noncoding RNAs (lncRNAs) in disease is incompletely understood, but their regulation of inflammation is increasingly appreciated. We addressed the extent of lncRNA involvement in inflammatory bowel disease (IBD) using biopsy-derived RNA-sequencing data from a large cohort of deeply phenotyped patients with IBD. Weighted gene correlation network analysis revealed gene modules of lncRNAs coexpressed with protein-coding genes enriched for biological pathways, correlated with epithelial and immune cell signatures, or correlated with distal colon expression. Correlation of modules with clinical features uncovered a module correlated with disease severity, with an enriched interferon response signature containing the hub lncRNA IRF1-AS1. Connecting genes to IBD-associated single nucleotide polymorphisms (SNPs) revealed an enrichment of SNP-adjacent lncRNAs in biologically relevant modules. Ulcerative colitis-specific SNPs were enriched in distal colon-related modules, suggesting that disease-specific mechanisms may result from altered lncRNA expression. The function of the IBD-associated SNP-adjacent lncRNA IRF1-AS1 was explored in human myeloid cells, and our results suggested IRF1-AS1 promoted optimal production of TNF-α, IL-6, and IL-23. A CRISPR/Cas9-mediated activation screen in THP-1 cells revealed several lncRNAs that modulated LPS-induced TNF-α responses. Overall, this study uncovered the expression patterns of lncRNAs in IBD that identify functional, disease-relevant lncRNAs.
| S-EPMC10967393 | biostudies-literature
Project description:Inflammatory bowel disease (IBD), comprised of ulcerative colitis and Crohn's disease, is believed to develop as a result of a deregulated inflammatory response to environmental factors in genetically susceptible individuals. Despite advances in understanding the genetic risks of IBD, associated single nucleotide polymorphisms have low penetrance, monozygotic twin studies suggest a low concordance rate, and increasing worldwide IBD incidence leave gaps in our understanding of IBD heritability and highlight the importance of environmental influences. Operating at the interface between environment and heritable molecular and cellular phenotypes, microRNAs (miRNAs) are a class of endogenous, small noncoding RNAs that regulate gene expression. Studies to date have identified unique miRNA expression profile signatures in IBD and preliminary functional analyses associate these deregulated miRNAs to canonical pathways associated with IBD pathogenesis. In this review, we summarize and discuss the miRNA expression signatures associated with IBD in tissue and peripheral blood, highlight miRNAs with potential future clinical applications as diagnostic and therapeutic targets, and provide an outlook on how to develop miRNA based therapies.
| S-EPMC4265084 | biostudies-literature
Project description:BackgroundInflammatory 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.MethodsIn the present study, we performed a genome-wide transcriptome profiling of lncRNAs and protein-coding genes in 96 colon pinch biopsies (inflamed and non-inflamed) extracted from multiple colonic locations from 45 patients (CD = 13, UC = 20, controls = 12) using an expression microarray platform.ResultsIn our 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 cases of inflamed CD and UC, we identified 438 and 745 differentially expressed lncRNAs, respectively, while in cases of the non-inflamed CD and UC, 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 their involvement in the immune response, pro-inflammatory cytokine activity and MHC protein complex.ConclusionsThe 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 suggest their potential as biomarkers in IBD.
| S-EPMC4437449 | biostudies-literature
Project description:Inflammatory bowel disease (IBD) is a chronic heterogeneous group of diseases that has undergone major advances in the understanding of its etiology and pathogenesis in recent years. The development of biologics had resulted in better overall management of the disease, including lower rates of surgery and better long-term clinical and patient-reported outcomes. Treatment modalities have either been newly developed or extrapolated from their approved use for a different indication. Modes of action and treatment targets have varied as well. Treatments such as vedolizumab and ustekinumab, as well as second-generation corticosteroids have been approved by the US Food and Drug Administration (FDA) for the treatment of IBD. Other agents are currently being developed at various stages of clinical trials including anti-adhesion agents such as etrolizumab and abrilumab, JAK inhibitors such as tofacitinib, and anti-trafficking molecules. Toll-like receptors and phosphatidylcholine are also new promising emerging targets that are being investigated in phase 3 clinical trials. It is projected that many therapies will become available in the coming years if supported by the results of current clinical trials. This will provide IBD patients with a wide array of options and allow physicians to choose the best therapies for each individual patient.
| S-EPMC6224002 | biostudies-literature
Project description:In the past decade, there have been fundamental advances in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors can mediate interactions between the environment and the genome; their study could provide new insight into the pathogenesis of IBD. We review recent progress in identification of genetic factors associated with IBD and discuss epigenetic mechanisms that could affect development and progression of IBD.
| S-EPMC3919211 | biostudies-literature
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.
2015-04-10 | GSE67106 | GEO
Project description:Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory disorder of the gastrointestinal tract that arises due to complex interactions between host genetic risk factors, environmental factors, and a dysbiotic gut microbiota. Although metagenomic approaches have attempted to characterise the dysbiosis occurring in IBD, the precise mechanistic pathways interlinking the gut microbiota and the intestinal mucosa are still yet to be unravelled. To deconvolute these complex interactions, a more reductionist approach involving microbial metabolites has been suggested. Bile acids have emerged as a key class of microbiota-associated metabolites that are perturbed in IBD patients. In recent years, metabolomics studies have revealed a consistent defect in bile acid metabolism with an increase in primary bile acids and a reduction in secondary bile acids in IBD patients. This review explores the evolving evidence that specific bile acid metabolites interact with intestinal epithelial and immune cells to contribute to the inflammatory milieu seen in IBD. Furthermore, we summarise evidence linking bile acids with intracellular pathways that are known to be relevant in IBD including autophagy, apoptosis, and the inflammasome pathway. Finally, we discuss how novel experimental and bioinformatics approaches could further advance our understanding of the role of bile acids and inform novel therapeutic strategies in IBD.
| S-EPMC8850271 | biostudies-literature
Project description:Pattern recognition receptors are essential mediators of host defense and inflammation in the gastrointestinal system. Recent data have revealed that toll-like receptors and nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs) function to maintain homeostasis between the host microbiome and mucosal immunity. The NLR proteins are a diverse class of cytoplasmic pattern recognition receptors. In humans, only about half of the identified NLRs have been adequately characterized. The majority of well-characterized NLRs participate in the formation of a multiprotein complex, termed the inflammasome, which is responsible for the maturation of interleukin-1? and interleukin-18. However, recent observations have also uncovered the presence of a novel subgroup of NLRs that function as positive or negative regulators of inflammation through modulating critical signaling pathways, including NF-?B. Dysregulation of specific NLRs from both proinflammatory and inhibitory subgroups have been associated with the development of inflammatory bowel disease (IBD) in genetically susceptible human populations. Our own preliminary retrospective data mining efforts have identified a diverse range of NLRs that are significantly altered at the messenger RNA level in colons from patients with IBD. Likewise, studies using genetically modified mouse strains have revealed that multiple NLR family members have the potential to dramatically modulate the immune response during IBD. Targeting NLR signaling represents a promising and novel therapeutic strategy. However, significant effort is necessary to translate the current understanding of NLR biology into effective therapies.
| S-EPMC4396872 | biostudies-literature
Project description:Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease are chronic, relapsing and remitting disorders of intestinal inflammation with potential systemic manifestations. Despite the availability of current biologics, such as anti-tumor necrosis factor (anti-TNF), anti-integrins, anti-interleukins and small molecules such as tofacitinib, the rates of primary and secondary treatment failure remain high in IBD. This highlights the importance of continued development of new therapeutic targets and modifications of existing ones to improve the treatment response rates and to also improve the safety profile and tolerability of these medications. In this review we will discuss novel treatment target agents including selective janus kinase (JAK) inhibitors, anti-interleukin (IL) (IL-12/IL-23), leukocyte trafficking/migrating inhibitors (such as sphingosine-1-phosphate receptor modulator) and other small molecules currently in development.
| S-EPMC8080036 | biostudies-literature