TALEN-mediated enhancer knockout influences TNFAIP3 gene expression and mimics a molecular phenotype associated with systemic lupus erythematosus

Wang, Shaofeng; Wen, Feng; Tessneer, Kandice L.; Gaffney, Patrick M.

doi:10.1038/gene.2016.4

Cited by 36 publications

(27 citation statements)

References 33 publications

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“…TALEN-mediated genome editing to disrupt specifically the TT4A enhancer region associated with SLE impaired its interaction with the A20 promoter by long-range DNA looping, thereby reducing A20 expression, indicating a causal contribution. 90 Two SNPs leading to nonsynonymous mutations in the A20 DUB domain were shown to reduce the NF-κB inhibitory potential of A20 upon overexpression. 91 More recently, loss-of-function mutations leading to A20 haploinsufficiency were shown to cause early-onset autoinflammatory disease that resembles Behçet's disease.…”

Section: A20mentioning

confidence: 99%

CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different

2017

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Polyubiquitination of proteins has a pivotal role in the regulation of numerous cellular functions such as protein degradation, DNA repair and cell signaling. As deregulation of these processes can result in pathological conditions such as inflammatory diseases, neurodegeneration or cancer, tight regulation of the ubiquitin system is of tremendous importance. Ubiquitination by E3 ubiquitin ligases can be counteracted by the activity of several deubiquitinating enzymes (DUBs). CYLD, A20 and OTULIN have been implicated as key DUBs in the negative regulation of NF-κB transcription factor-mediated gene expression upon stimulation of cytokine receptors, antigen receptors and pattern recognition receptors, by removing distinct types of polyubiquitin chains from specific NF-κB signaling proteins. In addition, they control TNF-induced cell death signaling leading to apoptosis and necroptosis via similar mechanisms. In the case of A20, also catalytic-independent mechanisms of action have been demonstrated to have an important role. CYLD, A20 and OTULIN have largely overlapping substrates, suggesting at least partially redundant functions. However, mice deficient in one of the three DUBs show significant phenotypic differences, indicating also non-redundant functions. Here we discuss the activity and polyubiquitin chain-type specificity of CYLD, A20 and OTULIN, their specific role in NF-κB signaling and cell death, the molecular mechanisms that regulate their activity, their role in immune homeostasis and the association of defects in their activity with inflammation, autoimmunity and cancer.

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Section: A20mentioning

confidence: 99%

CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different

2017

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“…As a proof of concept, we optimize and apply seven assays to characterize all known common genetic variants in the TNFAIP3 locus, a genetic locus associated with multiple autoimmune diseases 19 , and where disease-associated genetic and epigenetic features have been studied extensively [20][21][22][23][24] . We use cell lines derived from T cells, B cells, and monocytes (U937 or THP-1 monocyte cell lines, GM12878 or BJAB B cell lines, or Jurkat T cell line), representing three major cell lineages that can impact autoimmunity.…”

mentioning

confidence: 99%

Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features

et al. 2020

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Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/ disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants.

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“…This SNP is perfectly correlated (r 2 = 1.0) with another SLE risk-associated dinucleotide polymorphism, rs148314165 and rs200820567 (TT>A) located in a TNFAIP3-downstream enhancer, according to the Asian population data of the 1000 Genomes Project. The risk-associated minor allele A renders the enhancer to lack NF-κB binding and reduce TNFAIP3 expression in EBV-transformed B cells and HEK293T cells [59][60][61]. Fig.…”

Section: Discussionmentioning

confidence: 97%

Synergistic activation of NF-κB by TNFAIP3 (A20) reduction and UBE2L3 (UBCH7) augment that synergistically elevate lupus risk

2020

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Background: Systemic lupus erythematosus (SLE) is an autoimmune inflammatory rheumatic disease. SLE susceptibility is affected by multiple genetic elements, environmental factors, and their interactions. We aimed in this study to statistically and functionally characterize a gene-gene interaction (epistasis) recently documented to affect SLE risk. Methods: Two single-nucleotide polymorphisms, rs2230926 in TNFAIP3 (A20) gene and rs131654 in UBE2L3 (UBCH7) gene, were genotyped in all 3525 Korean participants, and their SLE risk association and epistasis were statistically analyzed by calculating odds ratio (OR), 95% confidence interval (CI), and P values in genotype comparisons between 1318 SLE patients and 2207 healthy controls. Furthermore, their effects on gene functions were assessed by comparatively examining separate and combined effects of TNFAIP3 and UBE2L3 knockdowns on NF-κB transcription factor activity in human cells. Results: SLE susceptibility is associated with TNFAIP3 rs2230926 (OR = 1.9, 95% CI 1.6-2.4, P = 8.6 × 10 −11) and UBE2L3 rs131654 (OR = 1.2, 95% CI 1.1-1.4, P = 1.1 × 10 −4) in a Korean population of this study. Their risk-associated alleles synergistically elevate SLE susceptibility in both multivariate logistic regression analysis (OR interaction = 1.6, P = 0.0028) and genotype-stratified analysis (OR interaction = 2.4), confirming the synergistic TNFAIP3-UBE2L3 interaction in SLE risk. Additionally, the SLE-susceptible alleles confer decreased TNFAIP3 expression (P = 1.1 × 10 −6 , n = 610) and increased UBE2L3 expression (P = 9.5 × 10 −11 , n = 475), respectively, in B cell analysis of the International HapMap Project individuals with adjustment for ethnicity. Furthermore, when compared with TNFAIP3 non-knockdown and UBE2L3 knockdown in human HeLa cells, TNFAIP3 knockdown and UBE2L3 non-knockdown synergistically increase three cytokines, CCL2, CXCL8 (IL8), and IL6, all regulated by NF-κB in the human TNFR signaling pathway.

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TALEN-mediated enhancer knockout influences TNFAIP3 gene expression and mimics a molecular phenotype associated with systemic lupus erythematosus

Cited by 36 publications

References 33 publications

CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different

CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different

Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features

Synergistic activation of NF-κB by TNFAIP3 (A20) reduction and UBE2L3 (UBCH7) augment that synergistically elevate lupus risk

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