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Setdb1 in required for intestinal epithelial differentiation and the prevention of intestinal inflammation

ABSTRACT: Setdb1 in required for intestinal epithelial differentiation and the prevention of intestinal inflammation

PROVIDER: PRJNA633811 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11811432.fastq.gz	Fastqsanger.gz
	SRR11811433.fastq.gz	Fastqsanger.gz
	SRR11811434.fastq.gz	Fastqsanger.gz
	SRR11811435.fastq.gz	Fastqsanger.gz
	SRR11811436.fastq.gz	Fastqsanger.gz

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Setdb1 in required for intestinal epithelial differentiation and the prevention of intestinal inflammation

Project description:The intestinal epithelium is a complex, constitutively renewing tissue composed of functionally distinct intestinal epithelial cells (IECs), whose specific cell fates are established and maintained through cell-specific activity of transcription factors, as well as precise gene silencing by chromatin compaction. By facilitating chromatin condensation through histone modification, SETDB1, a histone-lysine N-methyltransferase, is one of the central factors involved in regulation of epigenetic transcriptional repression. Therefore, we set out to study the potential roles of SETDB1 in intestinal epithelial homeostasis and inflammatory bowel disease (IBD). We used RNA-sequencing to profile gene expression changes in intestinal epithelial cells of mice with tamoxifen (TAM)-inducible (Villin-CreERT2) IEC-specific deletion of Setdb1 on day 2 post TAM-injection start, compared to TAM-treated wild-type littermates. We find an expression profile which indicates intestinal epithelial cell death and induction of type I interferon signaling, as a result of de-repression of endogenous retroviruses.

2021-02-22 | GSE150836 | GEO

SETDB1 is required for intestinal epithelial differentiation and the prevention of intestinal inflammation.

Project description:ObjectiveThe intestinal epithelium is a rapidly renewing tissue which plays central roles in nutrient uptake, barrier function and the prevention of intestinal inflammation. Control of epithelial differentiation is essential to these processes and is dependent on cell type-specific activity of transcription factors which bind to accessible chromatin. Here, we studied the role of SET Domain Bifurcated Histone Lysine Methyltransferase 1, also known as ESET (SETDB1), a histone H3K9 methyltransferase, in intestinal epithelial homeostasis and IBD.DesignWe investigated mice with constitutive and inducible intestinal epithelial deletion of Setdb1, studied the expression of SETDB1 in patients with IBD and mouse models of IBD, and investigated the abundance of SETDB1 variants in healthy individuals and patients with IBD.ResultsDeletion of intestinal epithelial Setdb1 in mice was associated with defects in intestinal epithelial differentiation, barrier disruption, inflammation and mortality. Mechanistic studies showed that loss of SETDB1 leads to de-silencing of endogenous retroviruses, DNA damage and intestinal epithelial cell death. Predicted loss-of-function variants in human SETDB1 were considerably less frequently observed than expected, consistent with a critical role of SETDB1 in human biology. While the vast majority of patients with IBD showed unimpaired mucosal SETDB1 expression, comparison of IBD and non-IBD exomes revealed over-representation of individual rare missense variants in SETDB1 in IBD, some of which are predicted to be associated with loss of function and may contribute to the pathogenesis of intestinal inflammation.ConclusionSETDB1 plays an essential role in intestinal epithelial homeostasis. Future work is required to investigate whether rare variants in SETDB1 contribute to the pathogenesis of IBD.

| S-EPMC7873423 | biostudies-literature

SETDB1 safeguards genome stability against necroptosis and bowel inflammation (ChIP-seq)

Project description:The aetiology of bowel inflammatory disease (IBD) is a multifactorial interplay between heredity and environment1-3. Here we report SETDB1, a histone methyltransferase (HMTs) for histone H3 lysine 9 trimethylation (H3K9me3) whose deficiency participates in the pathogenesis of IBD. We found that SETDB1 level decreased in IBD patients and that mice with reduced SETDB1 in intestinal stem cells (ISCs) developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability4, of which the loss in ISCs released repression of endogenous retrovirus (ERVs), the retrovirus-like elements with long repeats that comprise ~8% of genome5. Excessive viral mimicry generated by motivated ERVs triggered Z-DNA-binding protein 1 (ZBP1) dependent necroptosis, which irreversibly disrupted the homeostasis of epithelial barrier and promoted bowel inflammation. Of note, genome instability, reactive ERVs, upregulation of ZBP1 and necroptosis were seen in IBD patients. Pharmaceutic inhibition of RIP3 showed curative effect in SETDB1 deficient mice, suggesting therapy targeting ISC necroptosis may represent a new approach for severe IBD treatment.

2020-01-01 | GSE129173 | GEO

Setdb1 safeguards genome stability against stem cell necroptosis and bowel inflammation (RNA-seq)

2020-01-01 | GSE129172 | GEO

Aspirin and Inflammation: Mutations, Genes, Pathways and Prevention

Project description:Aspirin and Inflammation: Mutations, Genes, Pathways and Prevention

| PRJNA507060 | ENA

Aspirin and Inflammation: Mutations, Genes, Pathways and Prevention

Project description:Aspirin and Inflammation: Mutations, Genes, Pathways and Prevention

| PRJNA507059 | ENA

Setdb1 regulates proper differentiation of adult intestinal stem cells via restraining permissive chromatin structure and transcriptional variability

Project description:The histone methylase Setdb1 plays a pivotal role in embryonic stem cell maintenance and developmental lineage specification. However, its function in adult stem cells remains elusive. Here we show that conditional inactivation of Setdb1 in Lgr5+ intestinal stem cells alters the transcriptional programs of the progeny cell types and results in increased cell-to-cell transcriptional variability. Loss of Setdb1 blocked differentiation towards the absorptive enterocyte lineage, while the generation of secretory cell types was only marginally affected due to the activation of alternative developmental trajectories. Setdb1 inactivation did not alter H3K9 methylation at large heterochromatin domains but led to reduced localized modifications at islands of gene-rich areas around transposase-accessible chromatin regions, which have doubled in number, became broader and more heterogeneous in size. The results demonstrate that Setdb1 regulates intestinal stem cell properties and epithelial lineage specification by limiting chromatin accessibility at open genomic areas and controlling cell-to-cell transcriptional variability.

2024-10-21 | GSE279796 | GEO

Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation

Project description:Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation

| PRJNA857761 | ENA

Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation [scMultiomics]

Project description:Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation [scMultiomics]

| PRJNA1167747 | ENA

Intestinal response to prenatal inflammation

Project description:Intestinal response to prenatal inflammation

| PRJNA579380 | ENA