Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription

Ubieta, Kenia; García, Mireia; Grötsch, Bettina; Uebe, Steffen; Weber, Georg F.; Stein, Merle; Ekici, Arif B.; Schett, Georg; Mielenz, Dirk; Bözec, Aline

doi:10.1084/jem.20160514

Cited by 32 publications

(26 citation statements)

References 38 publications

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“…Surprisingly, differentially expressed genes in Fra-2-deficient macrophages were assembled in terms related to developmental functions (Supplemental Figure 1B). This confirms the essential function of Fra-2 during development (28)(29)(30). In contrast, GO cluster analysis based on differentially expressed genes in Fra-1-deficient macrophages revealed essential cellular pathways, such as wound response, proliferation, and responses to diverse stimuli (Figure 1, C-E, and Supplemental Figure 2).…”

Section: Resultssupporting

confidence: 62%

Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis

Hannemann¹,

Cao²,

Eriksson³

et al. 2019

Journal of Clinical Investigation

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Section: Resultssupporting

confidence: 62%

Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis

Hannemann¹,

Cao²,

Eriksson³

et al. 2019

Journal of Clinical Investigation

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“…Non-redundant features that distinguish BCR from TCR signalling might also sensitize developing B cells to altered Zn 2+ distribution. One such distinction is the B cell-specific requirement for FOXO1 degradation in order to suppress RAG expression at each positive selection checkpoint 19, 40, 41 . Progression through these developmental stages requires the sequential integration of multiple signals, determined by the activity of kinases and phosphatases.…”

Section: Discussionmentioning

confidence: 99%

An essential role for the Zn2+ transporter ZIP7 in B cell development

et al. 2019

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Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early-onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum–to–cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modelled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signalling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

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“…In the S1 Data (page 10–15), we discuss in greater detail 10 genes that are plausible targets of novel allergic disease variants identified in our study and that have a known function that is directly relevant to disease pathophysiology. In brief, the 10 genes are: ADAM15 , a metalloproteinase which cleaves the toll like receptor adaptor molecule TRIF [ 38 ] and the low affinity IgE receptor [ 39 ]; FOSL2 , a regulator of cell proliferation involved in B cell, Th17 cell and epidermal differentiation and function [ 40 – 42 ]; TRIM8 , a ligase involved in post-translational modifications of proteins, including ubiquitination of TAK1 [ 43 ] and TRIF [ 44 ]; BMPR2 , a receptor for the TGF-beta superfamily [ 45 ] that inhibits Smad-mediated signaling [ 46 ]; CD200R1 , a surface glycoprotein that interacts with CD200 [ 47 ], which is known to suppress the activation of various immune cells, including macrophages [ 48 ], mast cells [ 49 ], monocytes [ 50 ] and dendritic cells [ 51 ]; PRKCQ , a protein kinase involved in the development and function of Th17 cells [ 52 ], Th2 cells [ 53 ], Tregs [ 54 ] and type 2 innate lymphoid cells [ 55 ]; NOD2 , an intracellular pattern recognition receptor that upon activation by bacterial peptidoglycans [ 56 ] and viruses [ 57 ] promotes host defense through the production of inflammatory mediators [ 58 – 60 ]; SMAD4 , a central regulator of TGF-beta signaling [ 61 ], involved in Th2 cytokine production [ 62 ], Treg [ 63 ] and Th17 differentiation [ 64 ], the expression of selectin ligands [ 65 ] and of the pro-allergic cytokine IL-9 [ 66 ]; ABCA7 , a transporter protein that moves lipids across membranes [ 67 ], enhances phagocytosis of apoptotic cells by macrophages [ 68 ], promotes NKT cell development and function [ 69 ], and was suggested to play a role in keratinocyte differentiation [ 70 ]; and UBE2L3 , an essential compone...…”

Section: Discussionmentioning

confidence: 99%

Age-of-onset information helps identify 76 genetic variants associated with allergic disease

et al. 2020

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Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (r g =-0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

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Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription

Cited by 32 publications

References 38 publications

Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis

Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis

An essential role for the Zn2+ transporter ZIP7 in B cell development

Age-of-onset information helps identify 76 genetic variants associated with allergic disease

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