Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Analysis of whole-genome copy-number variation in Crohn's disease fistula tissue

ABSTRACT: Background: CrohnM-bM-^@M-^Ys disease is presently an incurable inflammatory bowel disease. Fistulae are extensions of the intestinal tract that may form connections with other organs. These are a common complication of CrohnM-bM-^@M-^Ys disease affecting up to 50% of patients with the most common including perianal and rectovaginal fistulae. The dysregulated growth observed in fistulae shares several major characteristics seen in the development of tumours. These similarities include epithelial-to-mesenchymal transition (EMT), invasive cell growth, increased extracellular matrix production and remodelling, up-regulated local expression of growth factors such as IGF-1 and the down-regulation of apoptosis pathways. Although several susceptibility loci have been described within CrohnM-bM-^@M-^Ys disease there is no individual gene or mutation that identifies susceptibility or the subsequent formation of fistulae within all people. Copy-number variation (CNV) is one mechanism that may explain much of this genetic complexity. CNV may be caused by a variety of mechanisms such as cycles of chromosomal breakage/fusion/bridging that are typical within chronically inflamed tissue. Interestingly CNV shows locus-specific mutation rates between individuals higher than that of SNPs and has been associated with complex Mendelian traits including disease susceptibility. In this current study we performed array comparative genomic hybridisation (aCGH) analysis of active fistulae resected from patients as part of a previous surgical intervention. As the control for comparison we employed tissue taken from the same patient within the same surgery at an uninvolved site of the gastrointestinal tract. This matched control was employed to better investigate CNV specific to the fistula tissue of each individual avoiding complications associated with the large number of CNV present within the healthy population. Major question addressed by the work: What are the differences in genetic copy-number within localised intestinal fistula tissue of individuals with CrohnM-bM-^@M-^Ys disease compared to healthy intestinal tissue from the same individual? Samples were selected from patients presenting with CrohnM-bM-^@M-^Ys Disease fistulae at Eastern Health Department of Gastroenterology and Hepatology (Arnold Street, Box Hill, Victoria, Australia). The 8 samples used in this study were formalin-fixed paraffin-embedded (FFPE) specimens following a surgical intervention to remove fistula tissue. To focus on changes within the individual patient we used tissue taken from the same surgery at an uninvolved region of the intestine as the matched control for CNV analysis.

ORGANISM(S): Homo sapiens

SUBMITTER: phillip parker

PROVIDER: E-GEOD-44275 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Crohn’s disease is presently an incurable inflammatory bowel disease. Fistulae are extensions of the intestinal tract that may form connections with other organs. These are a common complication of Crohn’s disease affecting up to 50% of patients with the most common including perianal and rectovaginal fistulae. The dysregulated growth observed in fistulae shares several major characteristics seen in the development of tumours. These similarities include epithelial-to-mesenchymal transition (EMT), invasive cell growth, increased extracellular matrix production and remodelling, up-regulated local expression of growth factors such as IGF-1 and the down-regulation of apoptosis pathways. Although several susceptibility loci have been described within Crohn’s disease there is no individual gene or mutation that identifies susceptibility or the subsequent formation of fistulae within all people. Copy-number variation (CNV) is one mechanism that may explain much of this genetic complexity. CNV may be caused by a variety of mechanisms such as cycles of chromosomal breakage/fusion/bridging that are typical within chronically inflamed tissue. Interestingly CNV shows locus-specific mutation rates between individuals higher than that of SNPs and has been associated with complex Mendelian traits including disease susceptibility. In this current study we performed array comparative genomic hybridisation (aCGH) analysis of active fistulae resected from patients as part of a previous surgical intervention. As the control for comparison we employed tissue taken from the same patient within the same surgery at an uninvolved site of the gastrointestinal tract. This matched control was employed to better investigate CNV specific to the fistula tissue of each individual avoiding complications associated with the large number of CNV present within the healthy population. Major question addressed by the work: What are the differences in genetic copy-number within localised intestinal fistula tissue of individuals with Crohn’s disease compared to healthy intestinal tissue from the same individual?

Project description:Background and aims: Mucosal abnormalities are potentially important in the primary pathogenesis of ulcerative colitis (UC). We investigated the mucosal transcriptomic expression profiles of biopsies from patients with UC and healthy controls (HC), taken from macroscopically non-inflamed tissue from the terminal ileum and three colonic locations with the objective of identifying abnormal molecules that might be involved in disease development. Methods: Whole-genome transcriptional analysis was performed on intestinal biopsies taken from 24 UC, 26 HC and 14 patients with CrohnM-bM-^@M-^Ys disease. Differential gene expression analysis was performed at each tissue location separately and results were then meta-analysed using FisherM-bM-^@M-^Ys method. Significantly differentially expressed genes were validated using qPCR. Gene location within the colon was determined using immunohistochemistry, subcellular fractionation, electron and confocal microscopy. DNA methylation was quantified by pyrosequencing. Results: Seven probes were abnormally expressed throughout the colon in UC patients with Family with sequence similarity member 5 C (FAM5C) being the most significantly underexpressed. Attenuated expression of FAM5C in UC was independent of inflammation, unrelated to phenotype or treatment, and remained low at rebiopsy approximately 23 months later. FAM5C is localised to the brush border of the colonic epithelium and expression is influenced by DNA methylation within its promoter. Conclusion: Genome-wide expression analysis of non-inflamed mucosal biopsies from UC patients identified FAM5C as significantly under-expressed throughout the colon in a major sub-set of patients with UC. Low levels of this gene could predispose to or contribute to the maintenance of the characteristic mucosal inflammation seen in this condition. Total RNA was extracted from the intestinal biopsies taken from macroscopically normal mucosa in the rectum, descending colon, ascending colon and terminal ileum in clinically quiescent Ulcerative colitis and Crohn's disease patients and compared to healthy controls. Normalized data for 26,261 probes out of 47,323 only. Criteria for inclusion not specified. The non-normalized matrix contains the complete non-normalized data for all probes.

Project description:16p11.2 microdeletion/microduplication syndrome is one of the common genetic causes of autism spectrum disorder, although it is not wholly penetrant with a wide range of phenotypic manifestations. We have previously explored the transcriptional consequences of the copy number variant (CNV) in cortical tissue of mouse models of the CNV within the syntenic 7qF3 region (Blumenthal et al 2014). We found that the strongest effects were from genes within the region itself, with no evidence for dosage compensation for any gene. Importantly, we found that global transcriptional effects due to the CNV were associated with multiple hypotheses for ASD pathogenesis, at the level of individual genes, networks and functional enrichments. To delineate tissue-specificity effects of the CNV, we embarked on exploration of the transcriptional landscape across multiple tissues for all mice from our earlier study. Specifically to disentangle brain-specific effects from others, we chose two additional brain tissues, namely Cerebellum and Striatum, as well as three other non-neuronal tissues, namely Liver, White Fat and Brown Fat. We present strand-specific RNAseq data for these five tissues in addition to the data for the Cortical tissue from our previous publication. Preliminary analyses of the data suggest that there are strong tissue-specific consequences of the CNV, with the effect being strongest in the Cortical tissue relative to other tissues, and observe low overlaps in differentially expressed genes across tissue. Furthermore, we see that the genes within the CNV region behave in a strong-tissue specific manner, with differences being more pronounced among the neuronal and non-neuronal tissues, relative to within tissue classes. Interestingly, we see that in non-neuronal tissues dosage compensation occurs for a handful of genes, when expressed. Finally, we see that genes within the CNV region show the strongest effects relative to the overall transcriptome in neuronal tissues and these effects are ameliorated in non-neuronal tissues.

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Analysis of whole-genome copy-number variation in Crohn's disease fistula tissue

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