Characterization of the molecular signature associated with the ablation of integrin α6 in IECs in the α6ΔIEC-TAM mouse model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE70700 | GEO | 2016/07/07
SECONDARY ACCESSION(S): PRJNA289395
REPOSITORIES: GEO
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Project description:Transcriptome analysis of mRNAs extracted from the rectal mucosa of WT and α6ÎIEC-TAM mice, 15 days after tamoxifen treatment Inflammatory bowel diseases (IBD) in humans are characterized by chronic inflammation and gastrointestinal tissue damage, caused by a combination of genetic and environmental factors. We show that the specific ablation of integrin α6 in intestinal epithelial cells (IECs) results in spontaneous colorectal inflammation in mice. In order to characterize the earlier molecular signature involved in the onset of inflammation, we performed Affymetrix microarrays and compare control versus α6ÎIEC-TAM transcriptomes after tamoxifen treatment. RNAs were prepared from rectal mucosa of 3 control mice treated with tamoxifen, 4 mutant mice treated with tamoxifen and 4 mutant mice treated with NaCl. The transcriptome analysis was performed using the Affymetrix Mouse Gene 1.0 ST arrays. Images were processed using affymetrix GeneChip® Command Console® Software (AGCC) (version 2.0) and numerical values were generated using Affymetrix Expression Console⢠Software (version 1.1).
2016-07-07 | E-GEOD-70700 | biostudies-arrayexpress
Project description:Inflammatory bowel diseases (IBD) in humans are characterized by chronic inflammation and gastrointestinal tissue damage, caused by a combination of genetic and environmental factors. It has been largely documented that IBD frequently lead to colorectal cancers (CRC). The identification of causative factors of IBD is thus essential to understand CRC progression and develop therapeutical approaches. Models have been described in which molecular alterations are combined with inflammatory treatments in order to recapitulate IBD-associated CRC. Here, we describe a mouse line, α6fl/fl Villin-Cre, in which inactivation of the gene encoding the integrin alpha-6 subunit (ITGA6) specifically in the intestinal mucosa results into chronic inflammation and intestinal carcinogenesis. In these mice, the loss of integrin alpha-6 beta-4, a receptor mediating the attachment of epithelial cells to laminins, leads to epithelial detachment, hyperplasia, chronic inflammation, rectal prolapses, and ultimately adenocarcinomas. Alterations of differentiation affecting mucus secreting (goblet) cells as well as changes in expression of essential intestinal transcription factors were detected. Thus alpha-6 beta-4 integrin is a key factor for the maintenance of intestinal integrity and its loss may represent a risk factor for tumor progression associated with IBD. Transcriptome analysis of RNA from normal versus inflamed and carcinomatous rectal mucosa of α6 integrin deficient intestinal epithelium mice was performed. RNAs were prepared from 5 adenocarcinomas, which were macrodissected from the rectal prolapses and 4 flanking inflamed rectal mucosa of 53-80 week-old α6fl/fl Villin-Cre mice. RNAs from normal rectal mucosa were obtained by rectum scraping from 4 matched control animals. The transcriptome analysis was performed using the Affymetrix Mouse Gene 1.0 ST arrays. Images were processed using affymetrix GeneChip® Command Console® Software (AGCC) (version 2.0) and numerical value were generated using Affymetrix Expression Console⢠Software (version 1.1).
2016-07-07 | E-GEOD-37749 | biostudies-arrayexpress
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. Analyses of histone acetylation in primary IECs from HDAC3FF (3 biologic replicates) and HDAC3ΔIEC (3 biologic replicates) mice were conducted utilizing ChIP-seq for H3K9Ac.
2013-12-02 | E-GEOD-50453 | biostudies-arrayexpress
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 (HDAC3?IEC) revealed that HDAC3 deficiency resulted in dysregulated gene expression coupled with alterations in histone acetylation. Critically, conventionally-housed HDAC3?IEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3?IEC 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 HDAC3?IEC 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 control HDAC3FF mice (3 biological replicates) and IEC-intrinsic knockout HDAC3?IEC mice (3 biological replicates).
2013-11-12 | E-GEOD-50188 | biostudies-arrayexpress
Project description:Background: We have applied an integrative approach, including classical genomic, microarray, and refined computational systems biology to study the regulatory pathways that involve DNA damage associated with typical drug preparations of Tamoxifen (TAM). We compared the effects of newly formulated Nano-emulsions of TAM (NanoTAM or N-TAM) on cultured HTB-20 cells to those of liquid preparations of TAM. Phenotypic screening was used to identify changes induced. Implicated regulatory pathways were systematically investigated by chromatin immunoprecipitation (ChIP) and DNA microarray analyses to identify alterations in protein-DNA interactions as well as genome-wide expression patterns. While liquid solutions of clinically used TAM can have a Z-score average of thousands of nm, after encapsulation and application of high pressure particle size was ~41 nm. ChIP-chip technology was used to classify promoter regions for target genes bound by E2F4 in human primary HTB-20 cells upon treatment with TAM or N-TAM. Specific drug effects were defined by comparing results obtained for Control/Control (CC) Control/Nano (CN), TAM (Drug)/Control (TC), and N-TAM (Drug)/Nano (TN). Functional effects noted included changes in apoptosis, cell proliferation, RNA processing, DNA damage, repair and replication, lipid and protein metabolism, transport, and transcriptional regulators. Cells treated with clinical TAM only expressed the ataxia telangiectasia mutated protein ATM as well as several histone proteins important for DNA damage sensing and activation of repair proteins, while N-TAM did not illicit this response.. In contrast N-TAM could not only enter the cells it could cross the inner mitochondrial membrane, induced more apoptosis and affecting mitochondrial DNA.
2021-06-25 | GSE178880 | GEO
Project description:Inflammatory bowel diseases (IBD) in humans are characterized by chronic inflammation and gastrointestinal tissue damage, caused by a combination of genetic and environmental factors. It has been largely documented that IBD frequently lead to colorectal cancers (CRC). The identification of causative factors of IBD is thus essential to understand CRC progression and develop therapeutical approaches. Models have been described in which molecular alterations are combined with inflammatory treatments in order to recapitulate IBD-associated CRC. Here, we describe a mouse line, α6fl/fl Villin-Cre, in which inactivation of the gene encoding the integrin alpha-6 subunit (ITGA6) specifically in the intestinal mucosa results into chronic inflammation and intestinal carcinogenesis. In these mice, the loss of integrin alpha-6 beta-4, a receptor mediating the attachment of epithelial cells to laminins, leads to epithelial detachment, hyperplasia, chronic inflammation, rectal prolapses, and ultimately adenocarcinomas. Alterations of differentiation affecting mucus secreting (goblet) cells as well as changes in expression of essential intestinal transcription factors were detected. Thus alpha-6 beta-4 integrin is a key factor for the maintenance of intestinal integrity and its loss may represent a risk factor for tumor progression associated with IBD.
2016-07-07 | GSE37749 | GEO
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).
2013-11-12 | E-GEOD-50189 | biostudies-arrayexpress
Project description:Microarray analysis of IECs from Tlr5+/+ and Tlr5–/– mice stimulated with either medium alone or flagellin (1 µg/ml); to elucidate TLR5-mediated immune responses in IECs. Keywords: ordered
2006-08-01 | GSE5112 | GEO
Project description:To further analyze the change of microRNA(miRNA) between normal peritoneal macrophage(PEC) and TAM from early tumor(12 days after 4T1 cell injection) or TAM from late tumor(21 days after 4T1 cell injection) , we employed Agilent mouse microRNA microarray Rel 12.0 as a discovery platform to identify miRNAs Total RNA from peritoneal macrophage and TAM of early tumor (tumor formed for 12days after BALB/c mice injected wth 4T1 cell) or TAM of late tumor(tumor formed for 21days after BALB/c mice injected with 4T1 cell) were extracted and analyzed using Agilent mouse microRNA microarray platform, and changes of miRNA were screened out. Agilent mouse microRNA microarray is designed for the profiling of mouse miRNA .627 mouse miRNA and 39 mouse virus-related miRNA can be detected by our microRNA microarray.
2015-03-31 | E-GEOD-67408 | biostudies-arrayexpress
Project description:Wheat cultivars ‘TAM 111’ and ‘TAM 112’ have been dominantly grown in the Southern U.S. Great Plains for many years due to their excellent, yet variable, drought tolerance. To identify the molecular basis and genetic control of drought tolerance in these two landmark cultivars, RNA-seq analysis was conducted to compare gene expression difference in flag leaves under fully irrigated (wet) and water deficient (dry) conditions. Of the 122,017 gene sequences assembled, 2,254 genes showed significantly altered expression patterns under dry and wet conditions in the two cultivars. TAM 111 had 593 and 1,532 dry-wet differentially expressed genes (DEGs), and TAM 112 had 777 and 1,670 at heading and grain-filling stages, respectively. The two cultivars have 1,214 (53.9%) dry-wet DEGs in common, which agreed with their excellent adaption to drought, but 438 and 602 dry-wet DEGs were respectively shown only in TAM 111 and TAM 112 suggested that each may have a specific mechanism to cope with drought. Annotation of all 2,254 genes with dry-wet expression difference found 1,855 have functions related to biosynthesis, stress responses, defense responses, transcription factors and cellular components related to ion or protein transportation and signal transduction. Comparing hierarchical structure of biological processes, molecule functions and cellular components revealed the significant regulation differences between TAM 111 and TAM 112, particularly for genes of phosphorylation and adenyl ribonucleotide binding, and proteins located in nucleus and plasma membrane. Comparing gene expressions involved in responses to stresses of water deprivation, heat and oxidative, ABA-induced signal pathway and transcription regulation found TAM 112 have more specific dry-wet DEGs than TAM 111 with most of them up-regulated, indicating that TAM 112 is more active than TAM 111 in response to drought. In addition, 399 dry-wet DEGs with unknown functions included 258 genes encoding predicted uncharacterized proteins and 141 unannotated genes with no similar sequences identified in the databases. These may represent novel genes related to drought response in TAM 111 or TAM 112. This research thus revealed different drought-tolerance mechanisms in TAM 111 and TAM 112 and identified useful drought tolerance genes for wheat adaption.
2020-08-29 | GSE157033 | GEO