The colitis risk gene C1orf106 (ROCS) regulates epithelial adherens junction stability
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Steven A. Carr
PROVIDER: MSV000081941 | MassIVE | Tue Jan 16 14:19:00 GMT 2018
REPOSITORIES: MassIVE
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Project description:Background & Aims: The contribution of genetics to the pathogenesis of inflammatory bowel disease (IBD) has been established by twin studies, targeted sequencing and genome-wide association studies (GWASs). This has yielded a plethora of risk loci with an aim to identify causal variants. Research on the genetic components of IBD has mainly focused on protein coding genes, thereby omitting other functional elements in the human genome i.e. the regulatory regions. Methods: Using acetylated histone 3 lysine 27 (H3K27ac) chromatin immunoprecipitation and sequencing (ChIP-seq), we identified tens of thousands of potential regulatory regions that are active in intestinal epithelium and immune cells, the main cell types involved in IBD. We correlated these regions with susceptibility loci for IBD. Results: We show that 45 out of 163 single nucleotide polymorphisms (SNPs) associated with IBD co-localize with active regulatory elements. In addition, another 47 IBD associated SNPs co-localize with active regulatory element via other SNP in strong linkage disequilibrium. Altogether 92 out of 163 IBD-associated SNPs can be connected with distinct regulatory element. This is 2.5 to 3.5 times more frequent than expected from random sampling. The genomic variation in these SNPs often creates or disrupts known binding motifs - thereby possibly affecting the binding affinity of transcriptional regulators and altering the expression of regulated genes. Conclusions: We show that in addition to protein coding genes, non-coding DNA regulatory regions, active in immune cells and in intestinal epithelium, are involved in IBD. H3K27ac ChIP-seq (ab4729, Abcam) profile of 7 intestinal epithelial samples
2013-12-06 | E-GEOD-51425 | biostudies-arrayexpress
Project description:Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory disease, and patients with IBD exhibit a higher risk of developing colorectal cancer (CRC). Epithelial barrier disruption is one of the major causes of inflammatory bowel disease (IBD) in which epigenetic modulations are pivotal elements. However, the epigenetic mechanisms underlying the epithelial barrier integrity regulation remain largely unexplored. Here, we investigated how SETD2, a histone H3K36 trimethyltransferase, maintains intestinal epithelial homeostasis under inflammatory conditions. GEO public database and IBD tissues were used to investigate the clinical relevance of SetD2 in IBD. To define the role of SetD2 in the colitis, we generated mice with epithelial-specific deletion of Setd2 (Setd2Vil-KO mice). Acute colitis was induced by 2% dextran sodium sulfate (DSS), and colitis-associated CRC was induced by injecting azoxymethane (AOM), followed by three cycles of 2% DSS treatments. Colon tissues were collected from mice and analyzed by histology, immunohistochemistry and immunoblots. Organoids were generated from Setd2Vil-KO and control mice, and were stained with 7-AAD to detect apoptosis. We isolated intestinal epithelial cells (IECs), performed RNA-seq and H3K36me3 ChIP-seq analysis to uncover the mechanism. Results were validated in functional rescue experiments by N-acetyl-l-cysteine (NAC) treatment and transgenes expression in IECs. SETD2 expression was decreased in IBD patients and DSS-treated colitis mice. Setd2Vil-KO mice had abnormal loss of mucosa-producing goblet cells and antimicrobial peptide (AMP)-producing Paneth cells, and promoted early intestinal inflammation development. Consistent with the reduced SETD2 expression in IBD patients, Setd2Vil-KO mice exhibited increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption. Intestinal permeability was markedly increased in Setd2Vil-KO mice. Setd2 ablation drived inflammation-associated CRC. Deletion of Setd2 resulted in excess reactive oxygen species (ROS), which led to cellular apoptosis and the defects in barrier integrity. N-acetyl-l-cysteine (NAC) treatment in Setd2Vil-KO mice rescued epithelial barrier injury and apoptosis. Moreover, overexpression of antioxidase PRDX6 in Setd2Vil-KO IECs largely alleviated the overproductions of ROS and improved the cellular survival. Deficiency of Setd2 specifically in the intestine aggravates epithelial barrier disruption and inflammatory response in colitis via a mechanism dependent on oxidative stress. More importantly, we show that Setd2 depletion results in excess ROS by directly down-regulating PRDX6, an antioxidant protein that inhibit excess ROS. Thus, our results highlight an epigenetic mechanism by which Setd2 mediates oxidative stress to modulate intestinal epithelial homeostasis.
2020-09-25 | GSE151967 | GEO
Project description:Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory disease, and patients with IBD exhibit a higher risk of developing colorectal cancer (CRC). Epithelial barrier disruption is one of the major causes of inflammatory bowel disease (IBD) in which epigenetic modulations are pivotal elements. However, the epigenetic mechanisms underlying the epithelial barrier integrity regulation remain largely unexplored. Here, we investigated how SETD2, a histone H3K36 trimethyltransferase, maintains intestinal epithelial homeostasis under inflammatory conditions. GEO public database and IBD tissues were used to investigate the clinical relevance of SetD2 in IBD. To define the role of SetD2 in the colitis, we generated mice with epithelial-specific deletion of Setd2 (Setd2Vil-KO mice). Acute colitis was induced by 2% dextran sodium sulfate (DSS), and colitis-associated CRC was induced by injecting azoxymethane (AOM), followed by three cycles of 2% DSS treatments. Colon tissues were collected from mice and analyzed by histology, immunohistochemistry and immunoblots. Organoids were generated from Setd2Vil-KO and control mice, and were stained with 7-AAD to detect apoptosis. We isolated intestinal epithelial cells (IECs), performed RNA-seq and H3K36me3 ChIP-seq analysis to uncover the mechanism. Results were validated in functional rescue experiments by N-acetyl-l-cysteine (NAC) treatment and transgenes expression in IECs. SETD2 expression was decreased in IBD patients and DSS-treated colitis mice. Setd2Vil-KO mice had abnormal loss of mucosa-producing goblet cells and antimicrobial peptide (AMP)-producing Paneth cells, and promoted early intestinal inflammation development. Consistent with the reduced SETD2 expression in IBD patients, Setd2Vil-KO mice exhibited increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption. Intestinal permeability was markedly increased in Setd2Vil-KO mice. Setd2 ablation drived inflammation-associated CRC. Deletion of Setd2 resulted in excess reactive oxygen species (ROS), which led to cellular apoptosis and the defects in barrier integrity. N-acetyl-l-cysteine (NAC) treatment in Setd2Vil-KO mice rescued epithelial barrier injury and apoptosis. Moreover, overexpression of antioxidase PRDX6 in Setd2Vil-KO IECs largely alleviated the overproductions of ROS and improved the cellular survival. Deficiency of Setd2 specifically in the intestine aggravates epithelial barrier disruption and inflammatory response in colitis via a mechanism dependent on oxidative stress. More importantly, we show that Setd2 depletion results in excess ROS by directly down-regulating PRDX6, an antioxidant protein that inhibit excess ROS. Thus, our results highlight an epigenetic mechanism by which Setd2 mediates oxidative stress to modulate intestinal epithelial homeostasis.
2020-09-25 | GSE151965 | GEO
Project description:The increased consumption of various beverages has been paralleled by an epidemic of several intestinal diseases around the world, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and colorectal cancer. Mounting evidence have shown that excessive consumption of beverages increases the risk of IBD and IBS. In addition, sugar-sweeter, food additives and food ingredients were identified to play important roles in these conditions. Consuming cold beverage is common among some people, especially in the youngsters. However, whether the cold stress contribute directly to host metabolism, gut barrier and gut-brain axis is unclear. In an intestinal function disorder model induced by cold water in mice, we investigated changes in gut transit, anxiety and depression like behavior. To evaluate the effect of cold water on gut barrier, we investigate the tight junctions in the colon. In addition, we employed RNA sequencing transcriptomic analysis to identify genes potentially driving the gut injury, and in parallel, examine the gut microbiota and metabolites in the feces.In an intestinal function disorder model induced by cold water in mice, we investigated changes in gut transit, anxiety and depression like behavior. To evaluate the effect of cold water on gut barrier, we investigate the tight junctions in the colon. In addition, we employed RNA sequencing transcriptomic analysis to identify genes potentially driving the gut injury, and in parallel, examine the gut microbiota and metabolites in the feces.
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Project description:Genetic variants in the DNMT3A locus have been associated with inflammatory bowel disease (IBD). DNMT3A is part of the epigenetic machinery physiologically involved in DNA methylation. We show that DNMT3A plays a critical role in maintaining intestinal homeostasis and gut barrier function. DNMT3A expression is downregulated in intestinal epithelial cells (IECs) from IBD patients and upon TNF treatment in murine intestinal organoids. Ablation of DNMT3A in Caco-2 cells results in global DNA hypomethylation, which is linked to impaired regenerative capacity, transepithelial resistance and intercellular junction formation. Genetic deletion of Dnmt3a in IECs (Dnmt3aΔIEC) in mice confirms the phenotype of an altered epithelial ultrastructure with shortened apical-junctional complexes, reduced Goblet cell numbers and increased intestinal permeability in the colon in vivo. Dnmt3aΔIEC mice suffer from increased susceptibility to experimental colitis, characterized by reduced epithelial regeneration. These data demonstrate a critical role for DNMT3A in orchestrating intestinal epithelial homeostasis and response to tissue damage and suggest an involvement of impaired epithelial DNMT3A function in the etiology of IBD.
2022-09-21 | GSE210714 | GEO
Project description:Genetic variants in the DNMT3A locus have been associated with inflammatory bowel disease (IBD). DNMT3A is part of the epigenetic machinery physiologically involved in DNA methylation. We show that DNMT3A plays a critical role in maintaining intestinal homeostasis and gut barrier function. DNMT3A expression is downregulated in intestinal epithelial cells (IECs) from IBD patients and upon TNF treatment in murine intestinal organoids. Ablation of DNMT3A in Caco-2 cells results in global DNA hypomethylation, which is linked to impaired regenerative capacity, transepithelial resistance and intercellular junction formation. Genetic deletion of Dnmt3a in IECs (Dnmt3aΔIEC) in mice confirms the phenotype of an altered epithelial ultrastructure with shortened apical-junctional complexes, reduced Goblet cell numbers and increased intestinal permeability in the colon in vivo. Dnmt3aΔIEC mice suffer from increased susceptibility to experimental colitis, characterized by reduced epithelial regeneration. These data demonstrate a critical role for DNMT3A in orchestrating intestinal epithelial homeostasis and response to tissue damage and suggest an involvement of impaired epithelial DNMT3A function in the etiology of IBD.
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2023-10-05 | PXD024688 | Pride
Project description:Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 ortholog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient (ctla-4-/-) zebrafish line. These mutant zebrafish exhibit reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, these findings offer substantial evidence linking CTLA-4 to IBD and establish a new model for investigating pathogenesis and potential treatments.
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Project description:Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 ortholog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient (ctla-4-/-) zebrafish line. These mutant zebrafish exhibit reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, these findings offer substantial evidence linking CTLA-4 to IBD and establish a new model for investigating pathogenesis and potential treatments.
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Project description:Background and Objectives: Antibiotic (ABx) therapy is associated with an increased risk for Crohn´s Disease but the underlying mechanisms are unknown. We observed high fecal serine protease activity (PA) to be a frequent side effect of ABx therapy in patients. The aim of the present study was to unravel whether this rise in PA may promote colitis development via detrimental effects on the large intestinal barrier. Design: Transwell experiments were used to assess the impact of high PA in ABx-treated patients or vancomycin/metronidazole (V/M)-treated mice on the epithelial barrier. Serine protease profiling was performed using LC-MS/MS analysis. The impact of high PA on the intestinal barrier in WT/IL10-/- mice and on colitis development in IL10-/- mice was investigated using V/M+/-oral serine protease inhibitor (AEBSF) treatment. Results: The ABx-induced high PA was found to be due to significantly increased levels of pancreatic proteases and to impair the epithelial barrier. In WT mice, the rise in PA caused a transient increase in intestinal permeability but did not affect susceptibility towards DSS-induced acute colitis. In IL10-/- mice, the rise in PA caused a lasting impairment of the intestinal barrier, which was associated with inflammatory activation of the large intestinal tissue. In the long term, the lasting increase in PA upon repeated V/M treatment aggravated colitis development in IL10-/-mice. Conclusion: High PA is a frequent adverse effect of ABx therapy which is detrimental to the large intestinal barrier and may contribute to the development of chronic inflammation in genetically susceptible individuals.
2018-05-11 | PXD007914 | Pride