Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models

Sokhi, Upneet K.; Liber, Mark P.; Frye, Laura; Park, Sungho; Kang, Ki‐Woon; Pannellini, Tania; Zhao, Baohong; Norinsky, Rada; Ivashkiv, Lionel B.; Gong, Shiaoching

doi:10.1038/s41467-018-03081-7

Cited by 29 publications

(26 citation statements)

References 49 publications

(70 reference statements)

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“…More work is required to identify further transcription factor binding sites within the A20 or DREAM promoter as well as other regulatory non-coding sequences such as enhancers (65,125) and microRNAs (62), and to decipher the relationship between DREAM and ER stress.…”

Section: Conclusion: the A20-dream Axis In Inflammationmentioning

confidence: 99%

Regulators of A20 (TNFAIP3): new drug-able targets in inflammation

Momtazi

Lambrecht

Naranjo

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

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Persistent activation of the transcription factor Nuclear factor-κB (NF-κB) is central to the pathogenesis of many inflammatory disorders, including those of the lung such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD). Despite recent advances in treatment, management of the inflammatory component of these diseases still remains suboptimal. A20 is an endogenous negative regulator of NF-κB signaling, which has been widely described in several autoimmune and inflammatory disorders and more recently in terms of chronic lung disorders. However, the underlying mechanism for the apparent lack of A20 in CF, COPD, and asthma has not been investigated. Transcriptional regulation of A20 is complex and requires coordination of different transcription factors. In this review we examine the existing body of research evidence on the regulation of A20, concentrating on pulmonary inflammation. Special focus is given to the repressor downstream regulatory element antagonist modulator (DREAM) and its nuclear and cytosolic action to regulate inflammation. We provide evidence that would suggest the A20-DREAM axis to be an important player in (airway) inflammatory responses and point to DREAM as a potential future therapeutic target for the modification of phenotypic changes in airway inflammatory disorders. A schematic summary describing the role of DREAM in inflammation with a focus on chronic lung diseases as well as the possible consequences of altered DREAM expression on immune responses is provided.

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Section: Conclusion: the A20-dream Axis In Inflammationmentioning

confidence: 99%

Regulators of A20 (TNFAIP3): new drug-able targets in inflammation

Momtazi

Lambrecht

Naranjo

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Along these lines, Mϕ rapidly adjust the temporal order of their responses to inflammatory challenges (eg, exposure to TNF or toll-like receptor (TLR) ligands) by transitioning from an acute proinflammatory to a subsequent homeostatic phenotype that promotes tissue repair and the resolution of inflammation 13. This is a tightly regulated process mediated by: (1) feedback loops that limit inflammatory cytokine production (eg, the interleukin (IL)-10/signal transducer and activator of transcription (STAT) 3 axis),14 (2) signalling brakes (eg, A20, ABINs, SOCS) that restrain inflammatory signalling15 16 and (3) chromatin remodelling that represses expression of proinflammatory genes 17–19. The result of these homeostatic molecular events is that following exposure to inflammatory stimuli (eg, TNF) macrophages typically display: (1) robust but transient expression of proinflammatory transcripts (eg, TNF, IL-1β, CXCL8) and (2) desensitisation (tolerance) to subsequent inflammatory stimulation.…”

Section: Introductionmentioning

confidence: 99%

TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: transcriptomic and epigenomic analysis

et al. 2019

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ObjectiveWe investigated genome-wide changes in gene expression and chromatin remodelling induced by tumour necrosis factor (TNF) in fibroblast-like synoviocytes (FLS) and macrophages to better understand the contribution of FLS to the pathogenesis of rheumatoid arthritis (RA).MethodsFLS were purified from patients with RA and CD14+ human monocyte-derived macrophages were obtained from healthy donors. RNA-sequencing, histone 3 lysine 27 acetylation (H3K27ac), chromatin immunoprecipitation-sequencing (ChIP-seq) and assay for transposable accessible chromatin by high throughput sequencing (ATAC-seq) were performed in control and TNF-stimulated cells.ResultsWe discovered 280 TNF-inducible arthritogenic genes which are transiently expressed and subsequently repressed in macrophages, but in RA, FLS are expressed with prolonged kinetics that parallel the unremitting kinetics of RA synovitis. 80 out of these 280 fibroblast-sustained genes (FSGs) that escape repression in FLS relative to macrophages were desensitised (tolerised) in macrophages. Epigenomic analysis revealed persistent H3K27 acetylation and increased chromatin accessibility in regulatory elements associated with FSGs in TNF-stimulated FLS. The accessible regulatory elements of FSGs were enriched in binding motifs for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interferon-regulatory factors (IRFs) and activating protein-1 (AP-1). Inhibition of bromodomain and extra-terminal motif (BET) proteins, which interact with histone acetylation, suppressed sustained induction of FSGs by TNF.ConclusionOur genome-wide analysis has identified the escape of genes from transcriptional repression in FLS as a novel mechanism potentially contributing to the chronic unremitting synovitis observed in RA. Our finding that TNF induces sustained chromatin activation in regulatory elements of the genes that escape repression in RA FLS suggests that altering or targeting chromatin states in FLS (eg, with inhibitors of BET proteins) is an attractive therapeutic strategy.

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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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Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models

Cited by 29 publications

References 49 publications

Regulators of A20 (TNFAIP3): new drug-able targets in inflammation

Regulators of A20 (TNFAIP3): new drug-able targets in inflammation

TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: transcriptomic and epigenomic analysis

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

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