A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [ATAC-seq]
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ABSTRACT:
PROVIDER: PRJNA1258201 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33413865_1.fastq.gz | Fastqsanger.gz | |||
| SRR33413865_2.fastq.gz | Fastqsanger.gz | |||
| SRR33413866_1.fastq.gz | Fastqsanger.gz | |||
| SRR33413866_2.fastq.gz | Fastqsanger.gz | |||
| SRR33413867_1.fastq.gz | Fastqsanger.gz |
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Project description:A20, encoded by the TNFAIP3 gene, is a protein linked to Crohn and celiac disease in humans. We show that mice expressing point mutations in A20’s M1-ubiquitin binding zinc-finger 7 (ZF7) domain spontaneously develop proximal enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveal expansion of TH17/22 cells and exuberant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7 mice. While deletion of IL-17A from A20ZF7 mice exacerbates enteritis, deletion of IL-22 abrogates intestinal epithelial cell hyperproliferation, barrier dysfunction, and alarmin expression. Colonization of adult germ-free mice with normal luminal flora drives duodenal IL-22 expression and duodenitis. A20ZF7 TH17/22 cells autonomously express more RORgammat and IL-22 after differentiation in vitro. ATAC sequencing identified an enhancer region upstream of the Il22 gene, and this enhancer demonstrated increased activating histone acetylation coupled with exaggerated Il22 transcription in A20ZF7 T cells. Acute inhibition of RORgammat normalized histone acetylation at this enhancer. Finally, CRISPR/Cas9-mediated ablation of A20ZF7 in human T cells increases RORgammat expression and IL22 transcription. These studies link A20’s M1-ubiquitin binding function with RORgammat expression, expansion of TH17/22 cells, and epigenetic activation of IL-22 driven enteritis.
2025-06-12 | GSE296203 | GEO
Project description:A20, encoded by the TNFAIP3 gene, is a protein linked to Crohn and celiac disease in humans. We show that mice expressing point mutations in A20’s M1-ubiquitin binding zinc-finger 7 (ZF7) domain spontaneously develop proximal enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveal expansion of TH17/22 cells and exuberant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7 mice. While deletion of IL-17A from A20ZF7 mice exacerbates enteritis, deletion of IL-22 abrogates intestinal epithelial cell hyperproliferation, barrier dysfunction, and alarmin expression. Colonization of adult germ-free mice with normal luminal flora drives duodenal IL-22 expression and duodenitis. A20ZF7 TH17/22 cells autonomously express more RORgammat and IL-22 after differentiation in vitro. ATAC sequencing identified an enhancer region upstream of the Il22 gene, and this enhancer demonstrated increased activating histone acetylation coupled with exaggerated Il22 transcription in A20ZF7 T cells. Acute inhibition of RORgammat normalized histone acetylation at this enhancer. Finally, CRISPR/Cas9-mediated ablation of A20ZF7 in human T cells increases RORgammat expression and IL22 transcription. These studies link A20’s M1-ubiquitin binding function with RORgammat expression, expansion of TH17/22 cells, and epigenetic activation of IL-22 driven enteritis.
2025-06-12 | GSE296201 | GEO
Project description:A20, encoded by the TNFAIP3 gene, is a protein linked to Crohn and celiac disease in humans. We show that mice expressing point mutations in A20’s M1-ubiquitin binding zinc-finger 7 (ZF7) domain spontaneously develop proximal enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveal expansion of TH17/22 cells and exuberant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7 mice. While deletion of IL-17A from A20ZF7 mice exacerbates enteritis, deletion of IL-22 abrogates intestinal epithelial cell hyperproliferation, barrier dysfunction, and alarmin expression. Colonization of adult germ-free mice with normal luminal flora drives duodenal IL-22 expression and duodenitis. A20ZF7 TH17/22 cells autonomously express more RORgammat and IL-22 after differentiation in vitro. ATAC sequencing identified an enhancer region upstream of the Il22 gene, and this enhancer demonstrated increased activating histone acetylation coupled with exaggerated Il22 transcription in A20ZF7 T cells. Acute inhibition of RORgammat normalized histone acetylation at this enhancer. Finally, CRISPR/Cas9-mediated ablation of A20ZF7 in human T cells increases RORgammat expression and IL22 transcription. These studies link A20’s M1-ubiquitin binding function with RORgammat expression, expansion of TH17/22 cells, and epigenetic activation of IL-22 driven enteritis.
2025-06-12 | GSE296200 | GEO
Project description:A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [scRNA-seq]
| PRJNA1258203 | ENA
Project description:A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [RNA-Seq]
| PRJNA1258204 | ENA
Project description:A20 is a negative regulator of NF-κB signaling, crucial to control inflammatory responses and ensure tissue homeostasis. A20 is thought to restrict NF-κB activation both by its ubiquitin-editing activity as by non-enzymatic activities. Besides its role in NF-κB signaling, A20 also acts as a protective factor inhibiting apoptosis and necroptosis. Because of the ability of A20 to both ubiquitinate and deubiquitinate substrates and its involvement in many cellular processes, we hypothesized that deletion of A20 might generally impact on protein levels, thereby disrupting cellular processes. We performed a differential proteomics study of bone marrow derived macrophages (BMDMs) from control and myeloid-specific A20 knockout mice, both in untreated conditions and after LPS and TNF treatment, and demonstrate proteome-wide changes in protein expression upon A20 deletion. Several inflammatory proteins are up-regulated in the absence of A20, even without an inflammatory stimulus. Depending on the treatment and the time, more proteins are regulated. Together these changes may affect multiple signaling pathways disturbing tissue homeostasis and inducing (autoimmune) inflammation, as suggested by genetic studies in patients.
2018-05-15 | PXD008726 | Pride
Project description:Unique and shared cytogenetic abnormalities have been documented for marginal zone lymphomas (MZLs) arising at different sites. Recently, homozygous deletions of the chromosomal band 6q23, involving the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) gene, a negative regulator of NF-kappa B, were described in ocular adnexal MZL, suggesting a role for A20 as a tumor suppressor in this disease entity. Here, we investigated inactivation of A20 by DNA mutations or deletions in a panel of extranodal (EMZL), nodal (NMZL) and splenic (SMZL) MZLs. Inactivating mutations encoding truncated A20 proteins were identified in 6/32 (18.8%) MZLs, including 3/11 (27.3%) EMZLs, 2/9 (22.2%) NMZLs, and 1/12 (8.3%) SMZLs. Two additional unmutated non-splenic MZLs also showed mono- or biallelic A20 deletions by FISH and/or array-CGH. Thus, A20 loss by both somatic mutations and/or deletions represents a common genetic aberration across all MZL subtypes, which may contribute to lymphomagenesis by inducing constitutive NF-kappa B activation. Keywords: Genome variation profiling by SNP array 27 MZL samples. No technical replications.
2009-04-01 | E-GEOD-13989 | biostudies-arrayexpress
Project description:Objectives: Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods: CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A knock-in cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was adressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results: Genetic disruption of A20 DUB domain in human and murine myeoloid cells did not give rise to enhanced NF-κB signaling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions: We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.
2019-07-10 | GSE116780 | GEO
Project description:Purpose: The goals of this study are to compare the transcriptome profiling (RNA-seq) of different A20 expression in HCT116 cells, to find potiential target genes for A20 mediated immnue escape. Results: There were 352 genes altered after A20 was knocked out with the log-fold >2 or <-2 compared to WT cells, and p value<0.01 . And 143 genes changed after rescued the expression of A20 in A20-KO cells compared to A20-KO cells. Among these altered genes, 13 genes were changes consistently. Conclusion:Gain- and loss-A20 functional studies proved that A20 could decrease the ¡°eat-me¡± signal calreticulin (CRT) protein on cell membranes via stabilizing stanniocalcin 1 (STC1). Mechanistically, A20 inhibited the degradation of STC1 protein which could capture the CRT inside cell rather than to translocated to cell membrane.
2023-08-30 | GSE206390 | GEO
Project description:Genome wide transcriptional profiling on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.bgalactosidase transduced livers, before and 24 hours after 78% extended liver resection. Overexpression of the NF-kB inhibitory protein A20 improves recovery of liver function and mass following extended liver resection and severe liver ischemia reperfusion injury in mice. In this project, we explored effects of A20 using transcriptional profiling on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.bgalactosidase transduced livers, before and 24 hours after 78% extended liver resection.
2010-09-18 | GSE24203 | GEO