GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at super-enhancers

Li, Yapeng; Gao, Jinliang; Kamran, Mohammad; Harmacek, Laura; Leach, Sonia M.; O’Connor, Brian P.; Hagman, James; Huang, Hua

doi:10.1038/s41467-020-20766-0

Cited by 39 publications

(43 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AP1 activity is positively associated with the development of IgE-mediated allergic diseases, and AP1 inhibition can suppress allergic asthma symptoms [ 43 – 46 ]. To examine the allergenic role of AP1, we employed T-5224, a selective c-Fos/AP1 inhibitor produced by Aikawa et al based on the crystal structure of the AP1-DNA complex [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

Wang

Zhang

et al. 2021

J Transl Med

View full text Add to dashboard Cite

Background Activator protein-1 (AP1), a c-Fos–JUN transcription factor complex, mediates many cytobiological processes. c-Fos has been implicated in immunoglobulin (Ig)E activation of mast cells (MCs) via high-affinity IgE Fc receptor (FcεRI) binding. This study examined c-Fos involvement in MC activation and tested the effects of the c-Fos/AP1 inhibitor T-5224 on MCs activation and allergic responses. Methods In vitro studies were conducted with two MC model systems: rat basophilic leukemia cells (RBLs) and mouse bone marrow derived mast cells (BMMCs). MC degranulation and effector functions were examined with β-hexosaminidase release and cytokine secretion assays. c-Fos/AP1 was inhibited with T-5224. c-Fos activity was suppressed with short hairpin RNA targeting c-Fos (shFos). In vivo immune responses were evaluated in passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models, as well as in an oxazolone (OXA)-induced model of atopic dermatitis, a common allergic disease. Results c-Fos expression was elevated transcriptionally and translationally in IgE-stimulated MCs. c-Fos binding of the Egr1 (early growth response 1) promoter upregulated Egr1 transcription, leading to production of interleukin (IL)4. T-5224 reduced FcεRI-mediated MC degranulation (evidenced by β-hexosaminidase activity and histamine levels) and diminished EGR1 and IL4 expression. T-5224 attenuated IgE-mediated allergic responses in PCA and ASA models, and it suppressed MC-mediated atopic dermatitis in mice. Conclusion IgE binding can activate MCs via a c-Fos/Egr1/IL-4 axis. T-5224 suppresses MC activation in vitro and in vivo and thus represents a promising potential strategy for targeting MC activation to treat allergic diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

Wang

Zhang

et al. 2021

J Transl Med

View full text Add to dashboard Cite

show abstract

“…To identify potential machineries involved in allowing transcription of antisense of FCER1A, we analyzed gene configuration of FCER1A locus in FcεRIα-expressing bone marrow derived mast cells using NCBI Gene Expression Omnibus (GEO) datasets (GSE145542 and GSE145544)(Li et al, 2021). We found that binding signals for H3K4me3 and H3K27ac, two histone modification fashions with upregulating activities on gene transcription, are enriched at not only at 5’promoter regions of FCER1A- S as expected but also at putative 5’promoter flanking region of FCER1A- AS in BMMC with comparable peak levels (Fig 7a).…”

Section: Resultsmentioning

confidence: 99%

An overlapped natural antisense lncRNA FCER1A-AS controls anaphylactic reaction by promoting FcεRIα expression

Tang

Yin

Liang

et al. 2022

Preprint

View full text Add to dashboard Cite

Functioned as α-subunit of the high-affinity immunoglobulin E receptor (FcϵRIα), FcϵRIα plays a central role in the pathogenesis of Ig-E-mediated allergy and other IgE-related disorders. FcϵRIα is normally expressed only in limited spectrum of cells like basophils and mast cells, but the mechanism of controlling FcϵRIα expression in these cells is less well understood. In this study, we found fully overlapped natural antisense transcript (NATs) of FcϵRIα (FCER1A-AS) is co-expressed with cognate sense transcript (FCER1A-S) in IL-3 induced FcϵRIα-expressing cells or in high FcϵRIα-expressing cell line MC/9. When FCER1A-AS is selectively knocked down by CRISPR/RfxCas13d (CasRx) approach in MC/9, expression of mRNA and proteins of FCER1A-S is also markedly decreased. Furthermore, deficiency of FCER1A-AS along with lack of FCER1A-S expression is found in two different lines of gene-targeted mice in which FCER1A locus is disturbed at different sites. More importantly, the FCER1A-AS-deficient homozygous mice display similarly diminished anaphylactic reaction as FCER1A gene knockout mice. Thus, we uncovered in this investigation that the expression of FCER1A-S is positively regulated by co-expressed fully overlapped antisense transcript.

show abstract

“…A series of studies have shown that eRNA expression and enhancer activity precede transcriptional induction of inflammatory genes in response to LPS [39][40][41]. More recently, tamoxifen-induced ablation of lineage-determining transcription factor GATA2 has revealed that GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at SEs [42]. Interestingly, in mouse primary B lymphocytes upon B-cell receptor activation, a mathematical modeling revealed that higher fold change of mRNA induction is associated with DNA length of SE while threshold response (i.e., switchlike) response is predefined by the coexistence of PU.1 and nuclear factor (NF)-jB in the SE [43].…”

Section: Ses In Immune Cells and Nonimmune Cellsmentioning

confidence: 99%

Potential roles of super enhancers in inflammatory gene transcription

Higashijima

Kanki

2021

The FEBS Journal

View full text Add to dashboard Cite

Acute and chronic inflammation is a basic pathological event that contributes to atherosclerosis, cancer, infectious diseases, and immune disorders. Inflammation is an adaptive process to both external and internal stimuli experienced by the human body. Although the mechanism of gene transcription is highly complicated and orchestrated in a timely and spatial manner, recent developments in next-generation sequencing, genomeediting, cryo-electron microscopy, and single cell-based technologies could provide us with insights into the roles of super enhancers (SEs). Initially, SEs were implicated in determining cell fate; subsequent studies have clarified that SEs are associated with various pathological conditions, including cancer and inflammatory diseases. Recent technological advances have unveiled the molecular mechanisms of SEs, which involve epigenetic histone modifications, chromatin three-dimensional structures, and phaseseparated condensates. In this review, we discuss the relationship between Abbreviations 3C, chromosome conformation capture; ATAC-seq, assay for transposase-accessible chromatin using sequencing; BACH2, BTB domain and CNC homolog 2; BET, bromodomain and extra-terminal; BRD2/3/4, bromodomain containing 2/3/4/; BRDT, bromodomain testis associated; BRG1/SMARCA4, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; C/EBPa, CCAAT enhancer binding protein alpha; CBP, CREB binding protein; CCL, C-C motif chemokine ligand; CDK, cyclin-dependent kinase; ChIA-PET, chromatin interaction analysis by paired-end tag sequencing; ChIP-seq, chromatin immunoprecipitation followed by sequencing; CKIa, casein kinase 1A1; CRISPR, clustered regularly interspaced short palindromic repeats; CTCF, CCCTC-binding factor; CTD, C-terminal domain; CXCL, C-X-C motif chemokine ligand; EBF1, EBF transcription factor 1; EDN1, endothelin 1; ERG, ETS-related gene; eRNA, enhancer RNA; ES, embryonic stem; Esrrb, estrogen related receptor beta; GATA2, GATA binding protein 2; GR, nuclear receptor subfamily 3 group C member 1; GTF, general transcription factor; H3K27ac, acetylation of lysine 27 in histone H3; H3K27me3, trimethylation of lysine 27 in histone H3; H3K4me1, monomethylation of lysine 4 in histone H3; H3K4me2, dimethylation of lysine 4 in histone H3; H3K4me3, trimethylation of lysine 4 in histone H3; H3K9me2, dimethylation of lysine 9 in histone H3;

show abstract

GATA2 regulates mast cell identity and responsiveness to antigenic stimulation by promoting chromatin remodeling at super-enhancers

Cited by 39 publications

References 75 publications

Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

An overlapped natural antisense lncRNA FCER1A-AS controls anaphylactic reaction by promoting FcεRIα expression

Potential roles of super enhancers in inflammatory gene transcription

Contact Info

Product

Resources

About