Retinoic Acid Modulates PTGDR Promoter Activity

García-Sánchez, Antonio; Marcos-Vadillo, Elena; Sanz, Catalina; Hernández-Hernández, Laura; Cerutti-Müller, G; Garcia, Fabien; Lorente, F.; Isidoro‐García, María; Dávila, Ignacio

doi:10.18176/jiaci.0042

Cited by 3 publications

(10 citation statements)

References 35 publications

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“…On the other hand, the experimental data showed that the CCCC construction, which combines both -549C and -197C mutated alleles, caused a significant increase in the promoter activity at 12 and 36 hours (basal conditions). This increased promoter activity reinforces previous results showing that the CCC (-549, -441, -197) combination was associated with higher luciferase expression at 12 and 48 hours [ 32 ]. In addition, in our expression experiment, both CCCC and CCCT haplotypes showed higher expression levels that the CTCT wild-type PTGDR haplotype (-613, -549, -441 and -197 positions).…”

Section: Discussionsupporting

confidence: 90%

PTGDR gene expression and response to dexamethasone treatment in an in vitro model

et al. 2017

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Asthma is a multifactorial pathology influenced by environmental and genetic factors. Glucocorticoid treatment decreases symptoms by regulating genes involved in the inflammatory process through binding to specific DNA sequences. Polymorphisms located in the promoter region of the Prostaglandin D Receptor (PTGDR) gene have been related to asthma. We aimed to analyze the effect of PTGDR promoter haplotypes on gene expression and response to corticosteroid therapy. A549 lung epithelial cells were transfected with vectors carrying four different PTGDR haplotypes (CTCT, CCCC, CCCT and TCCT), and treated with dexamethasone. Different approaches to study the promoter activity (Dual Luciferase Reporter System), gene expression levels (qPCR) and cytokine secretion (Multiplexed Bead-based Flow Cytometric) were used. In addition, in silico analysis was also performed. Cells carrying the TCCT haplotype showed the lowest promoter activity (p-value<0.05) and mRNA expression levels in basal conditions. After dexamethasone treatment, cells carrying the wild-type variant CTCT showed the highest response, and those carrying the TCCT variant the lowest (p-value<0.05) in luciferase assays. Different transcription factor binding patterns were identified in silico. Moreover, differences in cytokine secretion were also found among different promoter haplotypes. Polymorphisms of PTGDR gene influence basal promoter activity and gene expression, as well as the cytokine secretory pattern. Furthermore, an association between these positions and response to corticoid treatment was observed.

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Section: Discussionsupporting

confidence: 90%

PTGDR gene expression and response to dexamethasone treatment in an in vitro model

et al. 2017

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“…However, the role of RA in asthma and allergy is still controversial, [11,12,14]. We have previously reported that RA activated the PTGDR promoter, identifying RAREs in the promoter region and showing that transcription motifs were affected by genetic variants [17]. In the present study, we report for the first time the molecular mechanism of regulation of PTGDR expression by RA.…”

Section: Discussionmentioning

confidence: 54%

“…The wild-type PTGDR cDNA (NM_000953) was cloned in pCMV6-entry (OriGene, Rockville, MD, USA). The constitutive cytomegalovirus promoter of pCMV6- PTGDR was replaced by each one of the four promoter sequences of PTGDR haplotypes: CTCT, CCCT, TCCT and CCCC (-613C>T, -549T>C, -441C>T and -197T>C positions) [17,18]. Sequences were confirmed by sequencing and transformed into SoloPackGold Competent cells ( E .…”

Section: Methodsmentioning

confidence: 99%

“…ChIP was performed using EZ-Magna ChIP A kit (Millipore, Burlington, MA, USA) on KU812 cells and human PBMCs isolated from subjects bearing the PTGDR haplotypes [17]. Immunoprecipitated DNA using RARα and RARβ antibodies (Santa Cruz Biotechnology, Dallas, TX, USA) and input samples were subjected to qPCR using primers spanning the -549C/T PTGDR -promoter.…”

Section: Methodsmentioning

confidence: 99%

“…RA activates nuclear retinoic acid receptors (RARα, β, γ), which dimerize with retinoid X receptors (RXRα, β, γ) and function as ligand-dependent transcriptional regulators by binding to RA response elements (RARE) on target genes [15,16]. We have previously shown that RA activates the PTGDR promoter; in addition, we have identified RAREs in the promoter region, and demonstrated that some transcription factor motifs were affected by genetic variants [17]. Considering our previous results, the objective of this study was to deeper explore the regulatory mechanisms involved in the expression of PTGDR by ATRA and its effect on cytokine production.…”

Section: Introductionmentioning

confidence: 99%

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PTGDR expression is upregulated through retinoic acid receptors (RAR) mechanism in allergy

et al. 2019

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Functional studies suggest that promoter polymorphisms of the Prostaglandin D Receptor ( PTGDR ) gene can be involved in asthma. All-trans Retinoic acid (ATRA) has also been linked to allergic diseases. We have previously described the PTGDR promoter activation mediated by ATRA through response elements (RARE) at position -549T> C. In this study we aimed to analyze the effect of retinoic acid (RA) on the expression of PTGDR , the production of cytokines as well as to evaluate the binding of RA receptors to RA-Response Elements (RARE) sequences. A549 cells were transfected with vectors carrying different PTGDR haplotypes and treated with all-Trans Retinoic Acid (ATRA). PTGDR expression was measured by qPCR. Chromatin Immunoprecipitation assays (ChIP) were performed in ATRA stimulated KU812 cells and in PBMCs of patients carrying CTCT, CCCC or CCCT haplotypes. In addition, a broad panel of cytokines was analyzed by cytometric bead assay in A549 cells. The expression of PTGDR increased in A549 cells transfected with PTGDR -variants. The CCCC haplotype showed a significantly higher expression compared with CTCT. However, we found that RA up-regulated PTGDR expression through RARα mainly in the CTCT variant. Experiments on PBMCs from allergic patients carrying the -549T and -549C variant of the PTGDR promoter after ATRA and RAR antagonist administration confirmed the modulation of PTGDR by ATRA. The cytokine analysis showed that IL4 and IL6 levels were significantly increased in A549 cells transfected with PTGDR . In addition, ATRA treatment decreased the levels of IL4, IL6 and TNFα in A549 cells, whereas it increased IL4 and TNFα levels in PTGDR -transfected cells. We observed genetic differences in the regulation of PTGDR by ATRA that could contribute to the phenotypic differences observed in allergic patients. Our findings showed that RAR modulation by PTGDR might have an impact on Th2 responses, suggesting that RAR could be a potential therapeutic target in allergic inflammation.

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Shared Genetic Architecture and Causal Relationship Between Asthma and Cardiovascular Diseases: A Large-Scale Cross-Trait Analysis

et al. 2022

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Background: Accumulating evidence has suggested that there is a positive association between asthma and cardiovascular diseases (CVDs), implying a common architecture between them. However, the shared genetic architecture and causality of asthma and CVDs remain unclear.Methods: Based on the genome-wide association study (GWAS) summary statistics of recently published studies, our study examined the genetic correlation, shared genetic variants, and causal relationship between asthma (N = 127,669) and CVDs (N = 86,995–521,612). Statistical methods included high-definition likelihood (HDL), cross-trait meta-analyses of large-scale GWAS, transcriptome-wide association studies (TWAS), and Mendelian randomization (MR).Results: First, we observed a significant genetic correlation between asthma and heart failure (HF) (Rg = 0.278, P = 5 × 10−4). Through cross-trait analyses, we identified a total of 145 shared loci between asthma and HF. Fifteen novel loci were not previously reported for association with either asthma or HF. Second, we mapped these 145 loci to a total of 99 genes whose expressions are enriched in a broad spectrum of tissues, including the seminal vesicle, tonsil, appendix, spleen, skin, lymph nodes, breast, cervix and uterus, skeletal muscle, small intestine, lung, prostate, cardiac muscle, and liver. TWAS analysis identified five significant genes shared between asthma and HF in tissues from the hemic and immune system, digestive system, integumentary system, and nervous system. GSDMA, GSDMB, and ORMDL3 are statistically independent genetic effects from all shared TWAS genes between asthma and HF. Third, through MR analysis, genetic liability to asthma was significantly associated with heart failure at the Bonferroni-corrected significance level. The odds ratio (OR) is 1.07 [95% confidence interval (CI): 1.03–1.12; p = 1.31 × 10−3] per one-unit increase in loge odds of asthma.Conclusion: These findings provide strong evidence of genetic correlations and causal relationship between asthma and HF, suggesting a shared genetic architecture for these two diseases.

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Retinoic Acid Modulates PTGDR Promoter Activity

Cited by 3 publications

References 35 publications

PTGDR gene expression and response to dexamethasone treatment in an in vitro model

PTGDR gene expression and response to dexamethasone treatment in an in vitro model

PTGDR expression is upregulated through retinoic acid receptors (RAR) mechanism in allergy

Shared Genetic Architecture and Causal Relationship Between Asthma and Cardiovascular Diseases: A Large-Scale Cross-Trait Analysis

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