Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mouse conditional intestinal epithelial Hnf4Ialpha knockout to investigate the role of HNF4alpha in the adult colon

ABSTRACT: Background & Aims: HNF4Î± is an important transcriptional regulator of hepatocyte and pancreatic function. Hnf4Î± deletion is embryonically lethal with severe defects in visceral endoderm formation, liver maturation and colon development. However, the precise role of this transcription factor in maintaining homeostasis of the adult intestine remains unclear. Herein, we aimed to elucidate the adult intestinal functions of Hnf4Î±. Methods: A conditional intestinal epithelial Hnf4Î± knockout mouse was generated. Histological abnormality of the colonic mucosa was assessed by immunodetection and Western. Changes in global gene expression and biological network were analyzed. Results: Hnf4Î± intestine null mice developed normally until reaching young adulthood. Crypt distortion became apparent in the Hnf4Î± null colon at 3 months of age followed by focal areas of crypt dropout, increased immune cell infiltrates, crypt hyperplasia and early signs of polyposis later in life. A gene profiling analysis identified cell death and cell cycle related to cancer as the most significant sets of genes altered in the Hnf4Î± colon null mice. Expression levels of the tight junction proteins claudin 4, 8 and 15 were altered early in the colon epithelium of Hnf4Î± mutants and correlated with increased barrier permeability to a molecular tracer that does not normally penetrate normal mucosa. Conclusion: These observations support a functional role for Hnf4Î± in protecting the colonic mucosa against the initiation of the changes resembling inflammatory bowel diseases and polyp formation. Experiment Overall Design: HNF4alpha was conditionally knockout in the mouse epithelial colon with the villin CRE. A total of 3 control and 3 mutant littermates individuals were sacrificed at 1 year of age. The colon was harvested and Total RNA was isolated from each individuals. Each RNA sample was independently used to generate probes to screen affymetrix chips.

ORGANISM(S): Mus musculus

SUBMITTER: Francois Boudreau

PROVIDER: E-GEOD-11759 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice.

Darsigny Mathieu M Babeu Jean-Philippe JP Dupuis Andrée-Anne AA Furth Emma E EE Seidman Ernest G EG Lévy Emile E Verdu Elena F EF Gendron Fernand-Pierre FP Boudreau François F

PloS one 20091029 10

<h4>Background</h4>Hnf4alpha, an epithelial specific transcriptional regulator, is decreased in inflammatory bowel disease and protects against chemically-induced colitis in mice. However, the precise role of this factor in maintaining normal inflammatory homeostasis of the intestine remains unclear. The aim of this study was to evaluate the sole role of epithelial Hnf4alpha in the maintenance of gut inflammatory homeostasis in mice.<h4>Methodology/principal findings</h4>We show here that specif ...[more]

PMID: 19898610

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Project description:Mouse models of intestinal crypt cell differentiation and tumorigenesis have been used to characterize the molecular mechanisms underlying both processes. DNA methylation is a key epigenetic mark and plays an important role in cell identity and differentiation programs and cancer. To get insights into the dynamics of cell differentiation and malignant transformation we have compared the DNA methylation profiles along the mouse small intestine crypt and early stages of carcinogenesis. Genome-scale analysis of DNA methylation together with microarray gene expression have been applied to compare intestinal crypt stem cells (EphB2positive), differentiated cells (EphB2negative), ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Compared with late stages, small intestine crypt differentiation and early stages of carcinogenesis display few and relatively small changes in DNA methylation. Hypermethylated loci are largely shared by the two processes and affect the proximities of promoter and enhancer regions, with enrichment in genes regulated by PRC2 and associated with the intestinal stem cell signature. The hypermethylation is progressive, with minute levels in differentiated cells, as compared with intestinal stem cells, and reaching full methylation in advanced stages. Hypomethylation shows different signatures in differentiation and cancer and is already present in the non-tumor tissue adjacent to the adenomas in ApcMin/+mice, but at lower levels than advanced cancers. Taking into account the parallelisms between human and mouse intestinal carcinogenesis, this study provides a reference framework to interpret the alterations found in human cancer. We have analyzed ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Samples were in triplicates, except for tissue adjacent to adenoma (in duplicates).

Dataset Information

Transcription profiling of mouse conditional intestinal epithelial Hnf4Ialpha knockout to investigate the role of HNF4alpha in the adult colon

Publications

Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice.

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