Intestinal epithelial cells from Crohn's Disease patients
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE72780 | GEO | 2015/12/01
SECONDARY ACCESSION(S): PRJNA295053
REPOSITORIES: GEO
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Project description:Crohn’s disease is a chronic, debilitating inflammatory bowel disease. Here we report a critical role for phospholipase C-β3 (PLC-β3) in intestinal homeostasis. In PLC-β3- deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-β3 deficiency in multiple non-hematopoietic cell types. PLC-β3 deficiency resulted in reduced Wnt/β-catenin signaling, which is essential for homeostasis and regeneration of the intestinal epithelium. PLC-β3 regulated the Wnt/β-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and potentially protein-protein interaction levels. PLC-β3- deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/β-catenin signaling. Reduced expression of PLC-β3 and its signature genes was found in biopsies of ileal Crohn’s disease patients. PLC-β regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that reduction of PLC-β3- mediated Wnt/β-catenin signaling contributes to the pathogenesis of ileal Crohn’s disease.
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Project description:Crohn’s disease is a chronic, debilitating inflammatory bowel disease. Here we report a critical role for phospholipase C-β3 (PLC-β3) in intestinal homeostasis. In PLC-β3- deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-3 deficiency in multiple non-hematopoietic cell types. PLC-β3 deficiency resulted in reduced Wnt/-catenin signaling, which is essential for homeostasis and regeneration of the intestinal epithelium. PLC-β3 regulated the Wnt/β-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and potentially protein-protein interaction levels. PLC-β3- deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/β-catenin signaling. Reduced expression of PLC-β3 and its signature genes was found in biopsies of ileal Crohn’s disease patients. PLC-β regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that reduction of PLC-β3- mediated Wnt/β-catenin signaling contributes to the pathogenesis of ileal Crohn’s disease.
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Project description:Crohn’s disease is a chronic, debilitating inflammatory bowel disease. Here we report a critical role for phospholipase C-β3 (PLC-β3) in intestinal homeostasis. In PLC-β3- deficient mice, exposure to oral dextran sodium sulfate induced lethality and severe inflammation in the small intestine. The lethality was due to PLC-3 deficiency in multiple non-hematopoietic cell types. PLC-β3 deficiency resulted in reduced Wnt/-catenin signaling, which is essential for homeostasis and regeneration of the intestinal epithelium. PLC-β3 regulated the Wnt/β-catenin pathway in small intestinal epithelial cells (IECs) at transcriptional, epigenetic, and potentially protein-protein interaction levels. PLC-β3- deficient IECs were unable to respond to stimulation by R-spondin 1, an enhancer of Wnt/β-catenin signaling. Reduced expression of PLC-β3 and its signature genes was found in biopsies of ileal Crohn’s disease patients. PLC-β regulation of Wnt signaling was evolutionally conserved in Drosophila. Our data indicate that reduction of PLC-β3- mediated Wnt/β-catenin signaling contributes to the pathogenesis of ileal Crohn’s disease.
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Project description:The development and severity of inflammatory bowel diseases (IBD) and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that intestinal epithelial cells (IECs) isolated from IBD patients exhibit decreased expression of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3). Further, genome-wide analyses of murine IECs that lack HDAC3 (HDAC3ΔIEC) revealed that HDAC3 deficiency resulted in dysregulated gene expression coupled with alterations in histone acetylation. Critically, conventionally-housed HDAC3ΔIEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3ΔIEC mice exhibited significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 plays a central role in maintaining intestinal homeostasis. Strikingly, rederivation of HDAC3ΔIEC mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis, and intestinal barrier function were largely restored in the absence of commensal bacteria. Collectively, these data indicate that the HDAC3 is a critical factor that integrates commensal bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis. In this study, we performed gene expression profiling to examine how the transcriptional profiles in primary live, EpCAM+ IECs from the large intestine differed between germ-free control HDAC3FF mice (3 biological replicates) and germ-free IEC-intrinsic knockout HDAC3ΔIEC mice (3 biological replicates).
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