Dissection and Function of Autoimmunity-associated TNFAIP3 (A20) Gene Enhancers in Humanized Mouse Models [ChIP-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA413386 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6132672.fastq.gz | Fastqsanger.gz | |||
| SRR6132673.fastq.gz | Fastqsanger.gz | |||
| SRR6132674.fastq.gz | Fastqsanger.gz |
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Project description:Enhancers affect gene expression and disease. Little is known about enhancers that regulate human disease-associated genes in their native chromosomal context in primary cells relevant for pathogenesis. We used a BAC transgenic approach combined with CRISPR- and recombineering-mediated genome editing to dissect enhancers that regulate human TNFAIP3/A20, which is tightly linked with autoimmune diseases, in vivo and in primary immune cells. >20 enhancers in the A20 superenhancer were redundant; A20 expression was regulated by a topologically associating subdomain (sub-TAD) that harbors 5 enhancers. Deletion of this sub- TAD enhanced inflammatory responses and autoantibody production, establishing its functional importance in vivo. We identified cell- and activation-specific enhancers within this sub-TAD, including a key role for an enhancer harboring a proposed causal SLE-associated SNV. These findings map genomic regions that regulate human A20 expression to prevent inflammatory pathology and autoimmunity, and provide a platform for causally linking enhancers and SNVs with disease phenotypes.
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Project description:Early-onset complex autoimmunity can arise from monogenic activating mutations in inflammatory signalling pathways or loss of function mutations of immunoregulatory molecules. We sought to define the molecular basis of severe early-onset autoimmunity, characterised by autoimmune diabetes, cytopenias, hepatitis, enteropathy and interstitial lung disease, in a child without pathogenic variants in STAT3 and FOXP3. We employed whole exome sequencing, together with in vitro assays of tumor necrosis factor-alpha (TNF-α) signalling and response, including RNA sequencing, in patient fibroblasts. We identified a novel de novo heterozygous variant in TNFAIP3, which encodes A20 - a key negative regulator of the NF-κB transcriptional induction pathway. The p.V489Afs*7 variant reduced A20 protein expression and resulted in hyperresponsiveness of TNF-α signal transduction. This was accompanied by significant enhancement of TNF-α induced NF-κB target gene expression. There was an excellent clinical response to matched unrelated haematopoietic stem cell transplantation (HSCT), with resolution of all pathological features except diabetes. This case reveals a novel association between a previously unreported heterozygous TNFAIP3 mutation and the development of early-onset complex autoimmunity, validating existing evidence from both genome-wide association studies and conditional murine knockout models that implicates TNFAIP3 in autoimmune pathogenesis. This case also expands the clinical spectrum of germline A20 haploinsufficiency, recently identified in a cohort of patients with Behçet’s-like autoinflammatory disease, and shows that correction of the molecular defect within the haematopoietic cell compartment may be a viable treatment option for severe clinical manifestations.
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Project description:Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 33 HA20 patients, we show that heterozygous TNFAIP3 loss skews immune repertoires towards lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas.
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Project description:Feedback mechanisms regulate immune activation and prevent excessive tissue damage. TNFAIP3, also known as A20, serves as a crucial brake on inflammation, and mutations or haploinsufficiency of this gene are linked to diseases characterized by inappropriate inflammation. In this study, we document highly conserved patterns of cell type-specific gene expression, regulation, and induction of TNFAIP3, and employ transgenic and gnotobiotic mouse models to investigate how adaptive immunity and the gut microbiome contribute to pathology arising from impaired A20 function. Contrary to our expectations, systemic inflammation resulting from Tnfaip3 deficiency in CD11c (Itgax)-expressing cells developed independently of autoreactive antibodies, B cells, and T cells. The microbiome also proved dispensable for disease manifestations in these models. These findings suggest that in diseases caused by insufficient TNFAIP3/A20 activity, autoantibodies may reflect a downstream consequence of disease rather than a causative driver, suggesting autoinflammatory rather than autoimmune pathology. These insights carry therapeutic implications for the treatment of TNFAIP3-associated diseases.
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Project description:Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). Single-cell sequencing reveals “pre-lymphoma” transcription signatures in lymphocytes of HA20 patients.
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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.
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Project description:To investigate the impact of A20 on testosterone synthesis in the context of age-related inflammation, we employed lentiviral constructs to establish TNFAIP3-overexpressing TM3 cell lines. Subsequently, we conducted gene expression profiling analysis using RNA-seq data obtained from both normal TM3 cells and TNFAIP3-overexpressing TM3 cells.
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Project description:A20 (TNFAIP3) is genetically associated with both Psoriasis and Psoriatic Arthritis in humans. We find that induced deletion of A20 (Tnfaip3) in keratinocytes leads to fully penetrant psoriatic cutaneous inflammation and Psoriatic Arthritis-like joint disease in adult mice. To determine the early molecular pathways that trigger skin and joint inflammation, we performed transcriptomic profiling of epidermal gene expression 1 week following induced deletion of keratinocyte A20 in adult mice. Pathways analysis identified elevation of genes associated with MyD88-dependent and antiviral signaling following keratinocyte A20 deletion. Using compund mutants that prevent keratinocyte MyD88 signaling or antiviral signaling from Type I interferon receptors, we found that keratinocyte MyD88 signaling is required for development of psoriatic skin and joint inflammation following keratinocyte A20 deletion. These results identify unrestrained MyD88 signaling as a key mediator of psoriatic inflammation and psoriatic arthritis-like pathology caused by deletion of keratinocyte A20 in adult mice.
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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
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