Differential programming of intestinal tissues in SETD2-/- mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA377860 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5311170.fastq.gz | Fastqsanger.gz | |||
| SRR5311253_1.fastq.gz | Fastqsanger.gz | |||
| SRR5311253_2.fastq.gz | Fastqsanger.gz | |||
| SRR5311254_1.fastq.gz | Fastqsanger.gz | |||
| SRR5311254_2.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2017-09-01 | GSE95664 | 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 | 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:To determine the molecular regulation of different subsets of ILC3s by Setd2, small intestinal NKp46- ILC3s (Thy1highCD45low NKp46-) and NKp46+ ILC3s (Thy1highCD45low NKp46+) from Setd2-deficient and control mice were subjected to assay for RNA-seq.
2022-02-23 | GSE182840 | GEO
Project description:To determine the molecular regulation of different subsets of ILC3s by Setd2, small intestinal NKp46- ILC3s (Thy1highCD45low NKp46-) and NKp46+ ILC3s (Thy1highCD45low NKp46+) from Setd2-deficient and control mice were subjected to assay for ATAC-seq.
2022-02-23 | GSE182832 | GEO
Project description:Differential programming of B cells in Aicda-/- mice
| PRJNA207339 | ENA
Project description:Setd2 is the only enzyme that catalyzes histone H3 lysine 36 trimethylation (H3K36me3) on virtually all actively transcribed protein-coding genes, and this mechanism is evolutionarily conserved from yeast to human. Setd2 and H3K36me3 have been revealed to be involved in many important biochemical mechanisms, including DNA repair, alternative mRNA splicing and transcription elongation. However, physiological function of Setd2 in the context of zebrafish development remains elusive. Here we generated zebrafish setd2 mutant lines through disrupting the majority of the protein. And mRNA profiles of wild-type (WT), Setd2(+/-) and Setd2(-/-) zebrafish embryos at 36hpf were generated by deep sequencing, providing an opportunity to uncover molecular programs and functions of Setd2.
2020-05-27 | GSE151238 | GEO
Project description:To investigate the function of SETD2 in SMAD4-mutant colorectal cancer, we induced colorectal cancer in mice with intestinal epithelium-specific knockout of SMAD4 and SETD2 using AOM/DSS treatment.
2023-11-21 | GSE228024 | GEO
Project description:To investigate the function of SETD2 in SMAD4-mutant colorectal cancer, we induced colorectal cancer in mice with intestinal epithelium-specific knockout of SMAD4 and SETD2 using AOM/DSS treatment.
2023-11-21 | GSE228023 | GEO
Project description:Patients with polycystic kidney disease (PKD) encounter a high risk of clear cell renal cell carcinoma (ccRCC), a malignant tumor with dysregulated lipid metabolism. SET domain–containing 2 (SETD2) has been identified as an important tumor suppressor gene in ccRCC. However, the role of SETD2 in tumorigenesis during the transition from PKD to ccRCC remains largely unexplored. Herein, we performed metabolomics, lipidomics, transcriptomics and proteomics with SETD2 loss induced PKD-ccRCC transition mouse model. To characterize biological responses triggered by SETD2 deletion during PKD-ccRCC transition at the protein level, we conducted global proteomics studies.
2023-10-31 | PXD038966 | Pride