The Histone Methyltransferase Setd2 Modulates Oxidative Stress to Attenuates Colonic Inflammation and Tumorigenesis [ChIP-Seq]
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ABSTRACT:
PROVIDER: PRJNA637901 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11945559.fastq.gz | Fastqsanger.gz | |||
| SRR11945560.fastq.gz | Fastqsanger.gz | |||
| SRR11945561.fastq.gz | Fastqsanger.gz | |||
| SRR11945562.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:The Histone Methyltransferase Setd2 Modulates Oxidative Stress to Attenuates Colonic Inflammation and Tumorigenesis
| PRJNA637900 | ENA
Project description:The Histone Methyltransferase Setd2 Modulates Oxidative Stress to Attenuates Colonic Inflammation and Tumorigenesis [RNA-Seq]
| PRJNA637903 | ENA
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: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:This SuperSeries is composed of the SubSeries listed below.
2020-09-25 | GSE151968 | GEO
Project description:BRG1 attenuates colonic inflammation and tumorigenesis through autophagy-dependent oxidative stress sequestration
| PRJNA557213 | ENA
Project description:The histone methyltransferase SETD2 is responsible for the transcription-coupled trimethylation of histone H3 lysine 36 (H3K36me3) on all protein-coding genes through its direct interaction with the elongating form of RNA polymerase II. In mice, Setd2 is required for embryonic development, as the Setd2-null mice are embryonic lethal due to impaired vascular remodeling. In human, SETD2 is frequently mutated in various types of cancer, thus representing one of the major chromatin-modification defects that drive tumorigenesis. Notably, recent studies suggest that, despite the central roles of their catalytic activities, many chromatin modifiers contain important non-catalytic (so-called “moonlighting”) functions, which are largely substantiated by their roles in protein-protein interactions. This notion is somewhat consistent with the observation that the cancer-associated SETD2 mutations are seemingly localized throughout the whole protein, thus raising a question whether the major function(s) of SETD2 is solely dependent on its methyltransferase activity. As an answer to this question, in this short report, we have established a site-specific Setd2 knock-in mouse model harboring a patient-derived, catalytic dead Setd2 and have provided clear evidence supporting that the requirement of Setd2 in mouse embryonic development is definitely dependent on its methyltransferase activity. However, it is also notable that, in comparison with the Setd2-null mice, the Setd2 catalytic dead mice showed slightly mild defects in embryonic development and gene expression changes, suggesting potential non-catalytic functions of Setd2, which could be studied in the future by using these different Setd2 mouse models.
2024-01-01 | GSE241154 | GEO
Project description:We report that BRG1, an ATPase subunit of the SWI/SNF chromatin remodeling complex, was required for the homeostatic maintenance of colonic epithelial cells (IECs) to prevent the inflammation and tumorigenesis. Consistent with the reduced BRG1 expression in IBD patients, adult mice with IEC ablation of BRG1 developed spontaneous colitis and exhibited increased susceptibility to mutagen-induced tumor growth. Conversely, BRG1 overexpression protected the mice from DSS-induced epithelial damage and subsequent oncogenesis. Mechanistically, BRG1 emerged as a key regulator that directly governs the transcription of Atg16l1, Ambra1, Atg7 and Wipi2, which are important for autophagosome biogenesis. Thus, defective autophagy in BRG1-deficient IECs resulted in excess reactive oxygen species (ROS), which led to the defects in cellular apoptosis and barrier integrity.
2019-09-09 | GSE135041 | GEO
Project description:H3K36me3 catalyzed by histone methyltransferase SETD2 is one of the most conserved epigenetic marks from yeast to mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor. Here, utilizing a liver-specific deletion of Setd2 mice model, we found that Setd2 depletion is sufficient to trigger hepatocarcinoma (HCC) spontaneously. Meanwhile, in a DEN-induced HCC model, Setd2 depletion significantly promoted tumor number and size. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also regulating lipid metabolism in liver. Setd2 deficiency down-regulated the expression of cholesterol efflux genes and caused lipid accumulation. ChIP-Seq analysis further revealed that Setd2 deletion induced AP-1 activation in liver, which was probably trigged by accumulated cholesterol. AP-1 is a well-known oncogene in HCC and inhibits p53 in Setd2-deficient cells. Taken together, we found the role of an important epigenetic gene in regulating cholesterol homeostasis and HCC, and revealed the underlying mechanisms.
2021-09-01 | GSE136742 | GEO
Project description:H3K36me3 catalyzed by histone methyltransferase SETD2 is one of the most conserved epigenetic marks from yeast to mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor. Here, utilizing a liver-specific deletion of Setd2 mice model, we found that Setd2 depletion is sufficient to trigger hepatocarcinoma (HCC) spontaneously. Meanwhile, in a DEN-induced HCC model, Setd2 depletion significantly promoted tumor number and size. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also regulating lipid metabolism in liver. Setd2 deficiency down-regulated the expression of cholesterol efflux genes and caused lipid accumulation. ChIP-Seq analysis further revealed that Setd2 deletion induced AP-1 activation in liver, which was probably trigged by accumulated cholesterol. AP-1 is a well-known oncogene in HCC and inhibits p53 in Setd2-deficient cells. Taken together, we found the role of an important epigenetic gene in regulating cholesterol homeostasis and HCC, and revealed the underlying mechanisms.
2021-09-01 | GSE136743 | GEO