Systemic lupus erythematosus variants modulate the function of an enhancer upstream of TNFAIP3

Pasula, Satish; Gopalakrishnan, Jaanam; Fu, Yao; Tessneer, Kandice L.; Wiley, Mandi M.; Pelikan, Richard; Kelly, Jennifer A.; Gaffney, Patrick M.

doi:10.3389/fgene.2022.1011965

Cited by 7 publications

(4 citation statements)

References 41 publications

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“…The levels of C/EBPB expression is also positively correlated to the SLEDAI score [38]. Pasula et al later reported that CEBPB binding to the enhancer region of tumor necrosis factor alpha-inducible protein 3 (TNFAIP3, a negative regulator of pro-inflammatory stimulation) is required for its expression, while the TNFAIP3 locus has been shown to be associated with SLE by many studies [41]. Direct involvement of CEBPB in LN was discovered by Wang's group [42].…”

Section: Cebpb Enhanced Inflammasome Activity In the Pathogenesis Of Lnmentioning

confidence: 99%

Transcription Factors in the Pathogenesis of Lupus Nephritis and Their Targeted Therapy

Shao,

Shao

2024

IJMS

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Systemic lupus erythematosus (SLE) is a prototype inflammatory autoimmune disease, characterized by breakdown of immunotolerance to self-antigens. Renal involvement, known as lupus nephritis (LN), is one of the leading causes of morbidity and a significant contributor to mortality in SLE. Despite current pathophysiological advances, further studies are needed to fully understand complex mechanisms underlying the development and progression of LN. Transcription factors (TFs) are proteins that regulate the expression of genes and play a crucial role in the development and progression of LN. The mechanisms of TF promoting or inhibiting gene expression are complex, and studies have just begun to reveal the pathological roles of TFs in LN. Understanding TFs in the pathogenesis of LN can provide valuable insights into this disease’s mechanisms and potentially lead to the development of targeted therapies for its management. This review will focus on recent findings on TFs in the pathogenesis of LN and newly developed TF-targeted therapy in renal inflammation.

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Section: Cebpb Enhanced Inflammasome Activity In the Pathogenesis Of Lnmentioning

confidence: 99%

Transcription Factors in the Pathogenesis of Lupus Nephritis and Their Targeted Therapy

Shao,

Shao

2024

IJMS

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“…The gene TNFAIP3 is a likely target of the discovered enhancer, as it is a major negative regulator of pro-inflammatory nuclear factor kappa B (NF-κB) signaling, which is associated with many autoimmune diseases ( 137 ). Moreover, the risk allele (A/A) in the enhancer dramatically disrupts NF-κB binding and inhibits long-range DNA looping of the enhancer to the TNFAIP3 promoter, effectively decreasing TNFAIP3 expression and increasing IL20RA and IFNGR1 expression through TALEN (transcription activation-like effector nuclease)-mediated genome editing, HiChIP, 3C-qPCR, and dual-luciferase reporter assays ( 85 , 138 ). TNFAIP3 loss-of-function mutations result in elevated inflammatory responses, autoantibody production, and inflammatory arthritis in humanized mouse models ( 86 , 139 ).…”

Section: D Genome Disorganization In Autoimmune Diseasesmentioning

confidence: 99%

3D genome organization and epigenetic regulation in autoimmune diseases

Qiu,

Feng,

Jiang

et al. 2023

Front. Immunol.

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Three-dimensional (3D) genomics is an emerging field of research that investigates the relationship between gene regulatory function and the spatial structure of chromatin. Chromatin folding can be studied using chromosome conformation capture (3C) technology and 3C-based derivative sequencing technologies, including chromosome conformation capture-on-chip (4C), chromosome conformation capture carbon copy (5C), and high-throughput chromosome conformation capture (Hi-C), which allow scientists to capture 3D conformations from a single site to the entire genome. A comprehensive analysis of the relationships between various regulatory components and gene function also requires the integration of multi-omics data such as genomics, transcriptomics, and epigenomics. 3D genome folding is involved in immune cell differentiation, activation, and dysfunction and participates in a wide range of diseases, including autoimmune diseases. We describe hierarchical 3D chromatin organization in this review and conclude with characteristics of C-techniques and multi-omics applications of the 3D genome. In addition, we describe the relationship between 3D genome structure and the differentiation and maturation of immune cells and address how changes in chromosome folding contribute to autoimmune diseases.

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“…For example, TNFAIP3 encodes the AP20 enzyme, a known regulator of NFkB-mediated immune activation 36 and pro-IL-1β processing 37,38 . The association signals at the TNFAIP3 gene locus have been resolved to TNFAIP3 using experimental [39][40][41] or in silico 42 methods for some of the immune-mediated diseases.…”

Section: Genetic Associations Of Crispr Screening Hits With Immune-me...mentioning

confidence: 99%

A genome-wide CRISPR screen supported by human genetics identifies theTNRC18gene locus as a novel regulator of inflammatory signaling

Rahimov,

Ghosh,

Petiwala

et al. 2023

Preprint

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Interleukin-1β (IL-1β) is dysregulated in many chronic inflammatory diseases, yet the genetic factors influencing IL-1β production and signaling remain largely unknown. Myeloid-derived cells are the primary producers of IL-1β, prompting a genome-wide CRISPR knockout screen in the human myeloid-derived U937 cell model, treated with lipopolysaccharide (LPS) to mimic inflammatory conditions, and sorted for high and low intracellular IL-1β levels. A total of 295 genes were identified as regulators of IL-1β production, including known mediators, such as TLR4, JAK-STAT, IL-10 receptor, and the Cullin ring finger ligase complex. Notably, 57 out of the 295 genes overlapped with loci associated with human inflammatory diseases, including theTNRC18gene on chromosome 7p22.1 associated with multiple diseases in the Finnish population. U937 cells engineered with the homozygous rs748670681 risk allele associated with inflammatory bowel disease, demonstrated decreased levels of mRNA forTNRC18and an adjacent geneWIPI2, reduction in LPS-dependent gene activation and cytokine production, but elevation of interferon-responsive gene programs. Transcriptomic profiles for individual knockouts ofTNRC18andWIPI2attributed the loss of LPS-dependent signaling primarily toTNRC18while the exacerbation of interferon signaling is a hallmark of loss ofWIPI2. Collectively, these findings delineate the global regulatory mechanisms of IL-1β production and provide molecular insights to the role of the rs748670681 variant as a pleiotropic risk factor for inflammatory diseases.

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Systemic lupus erythematosus variants modulate the function of an enhancer upstream of TNFAIP3

Cited by 7 publications

References 41 publications

Transcription Factors in the Pathogenesis of Lupus Nephritis and Their Targeted Therapy

Transcription Factors in the Pathogenesis of Lupus Nephritis and Their Targeted Therapy

3D genome organization and epigenetic regulation in autoimmune diseases

A genome-wide CRISPR screen supported by human genetics identifies theTNRC18gene locus as a novel regulator of inflammatory signaling

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