47 results found
Zhang Y, 2023, From gene identifications to therapeutic targets for asthma: Focus on great potentials of TSLP, ORMDL3, and GSDMB, Chinese Medical Journal Pulmonary and Critical Care Medicine, ISSN: 2772-5588
Zhang Y, Ma J, Du H, et al., 2023, The prognostic effect of ADH1B and ALDH2 in lung adenocarcinoma, 2023 ASCO Annual Meeting, Publisher: American Society of Clinical Oncology, ISSN: 0732-183X
Zhang Y, Liu Y, 2023, Editorial: chronic airway diseases, lung cancer, and their interaction, Frontiers of Medicine, Vol: 10, Pages: 1-3, ISSN: 1673-7342
Chang E, Wang Y, Zhu R, et al., 2023, General anesthetic action profile on the human prefrontal cortex cells through comprehensive single-cell RNA-seq analysis, iScience, Vol: 26, Pages: 1-19, ISSN: 2589-0042
The cellular and molecular actions of general anesthetics to induce anesthesia state and also cellular signaling changes for subsequent potential "long term" effects remain largely elusive. General anesthetics were reported to act on voltage-gated ion channels and ligand-gated ion channels. Here we used single-cell RNA-sequencing complemented with whole-cell patch clamp and calcium transient techniques to examine the gene transcriptome and ion channels profiling of sevoflurane and propofol, both commonly used clinically, on the human fetal prefrontal cortex (PFC) mixed cell cultures. Both propofol and sevoflurane at clinically relevant dose/concentration promoted "microgliosis" but only sevoflurane decreased microglia transcriptional similarity. Propofol and sevoflurane each extensively but transiently (<2 h) altered transcriptome profiling across microglia, excitatory neurons, interneurons, astrocytes and oligodendrocyte progenitor cells. Utilizing scRNA-seq as a robust and high-through put tool, our work may provide a comprehensive blueprint for future mechanistic studies of general anesthetics in clinically relevant settings.
Li J, Zheng Z, Liu Y, et al., 2023, IRAK-M has effects in regulation of lung epithelial inflammation, Respiratory Research, Vol: 24, Pages: 1-12, ISSN: 1465-9921
BackgroundEpithelial barrier is important for asthma development by shaping immune responses. Airway expressing-IL-1 receptor-associated kinase (IRAK)-M of Toll-like receptor pathway was involved in immunoregulation of airway inflammation through influencing activities of macrophages and dendritic cells or T cell differentiation. Whether IRAK-M has effect on cellular immunity in airway epithelial cells upon stimulation remains unclear.MethodsWe modeled cellular inflammation induced by IL-1β, TNF-α, IL-33, and house dust mite (HDM) in BEAS-2B and A549 cells. Cytokine production and pathway activation were used to reflect the effects of IRAK-M siRNA knockdown on epithelial immunity. Genotyping an asthma-susceptible IRAK-M SNP rs1624395 and measurement of serum CXCL10 levels were performed in asthma patients.ResultsIRAK-M expression was significantly induced in BEAS-2B and A549 cells after inflammatory stimulation. IRAK-M knockdown increased the lung epithelial production of cytokines and chemokines, including IL-6, IL-8, CXCL10, and CXCL11, at both mRNA and protein levels. Upon stimulation, IRAK-M silencing led to overactivation of JNK and p38 MAPK in lung epithelial cells. While antagonizing JNK or p38 MAPK inhibited increased secretion of CXCL10 in IRAK-M silenced-lung epithelium. Asthma patients carrying G/G genotypes had significantly higher levels of serum CXCL10 than those carrying homozygote A/A.ConclusionOur findings suggested that IRAK-M has effect on lung epithelial inflammation with an influence on epithelial secretion of CXCL10 partly mediated through JNK and p38 MAPK pathways. IRAK-M modulation might indicate a new insight into asthma pathogenesis from disease origin.
Zheng Z, Li J, Cui Y, et al., 2022, IRAK-M regulates proliferative and invasive phenotypes of lung fibroblasts, Inflammation, Vol: 46, Pages: 763-778, ISSN: 0360-3997
Lung fibroblasts play an important role in subepithelial fibrosis, one feature for airway remodeling. IL-1 receptor-associated kinase (IRAK)-M was shown to involve fibrosis formation in airways and lung through regulation of inflammatory responses. IRAK-M is expressed by lung fibroblasts, whether IRAK-M has direct impact on lung fibroblasts remains unclear. In this investigation, we evaluated in vitro effect of IRAK-M on phenotypes of lung fibroblasts by silencing or overexpressing IRAK-M. Murine lung fibroblasts (MLg) were stimulated with house dust mite (HDM), IL-33, and transforming growth factor (TGF) β1. Techniques of small interfering RNA or expression plasmid were employed to silence or overexpress IRAK-M in MLg fibroblast cells. Proliferation, migration, invasiveness, and fibrosis-related events were evaluated. Significant upregulation of IRAK-M expression in MLg cells was caused by these stimuli. Silencing IRAK-M significantly increased proliferation, migration, and invasiveness of lung fibroblasts regardless of stimulating conditions. By contrast, IRAK-M overexpression significantly inhibited proliferation and motility of MLg lung fibroblasts. IRAK-M overexpression also significantly decreased the expression of fibronectin, collagen I, and α-SMA in MLg cells. Under stimulation with TGFβ1 or IL-33, IRAK-M silencing reduced MMP9 production, while IRAK-M overexpression increased MMP9 production. Modulation of IRAK-M expression affected cytokines production, either decreased or increased expression of TNFα and CXCL10 by the cells regardless of stimulation. Our in vitro data reveal that IRAK-M directly impacts on lung fibroblasts through modulation of cellular motility, release of inflammatory, and fibrotic cytokines of lung fibroblasts. These might suggest a new target by regulation of IRAK-M in slowing airway remodeling.
Zhang Y, 2021, Orosomucoid-like protein 3, rhinovirus and asthma, World Journal of Critical Care Medicine, Vol: 10, Pages: 170-182, ISSN: 2220-3141
The genetic variants of orosomucoid-like protein 3 (ORMDL3) gene are associated with highly significant increases in the number of human rhinovirus (HRV)-induced wheezing episodes in children. Recent investigations have been focused on the mechanisms of ORMDL3 in rhinovirus infection for asthma and asthma exacerbations. ORMDL3 not only regulates major human rhinovirus receptor intercellular adhesion molecule 1 expression, but also play pivotal roles in viral infection through metabolisms of ceramide and sphingosine-1-phosphate, endoplasmic reticulum (ER) stress, ER-Golgi interface and glycolysis. Research on the roles of ORMDL3 in HRV infection will lead us to identify new biomarkers and novel therapeutic targets in childhood asthma and viral induced asthma exacerbations.
Willis-Owen S, Domingo Sabugo C, Starren E, et al., 2021, Y disruption, autosomal hypomethylation and poor male lung cancer survival, Scientific Reports, Vol: 11, ISSN: 2045-2322
Lung cancer is the most frequent cause of cancer death worldwide. It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA–IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression, KDM5D. After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40–10.3, P = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4–2.0, P = 1.2 × 10–10). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.
Laura G, Liu Y, Fernandes K, et al., 2021, ORMDL3 regulates poly I:C induced inflammatory responses in airway epithelial cells, BMC Pulmonary Medicine, Vol: 21, ISSN: 1471-2466
Background:Oroscomucoid 3 (ORMDL3) has been linked to susceptibility of childhood asthma and respiratory viral infection. Polyinosinic-polycytidylic acid (poly I:C) is a synthetic analog of viral double-stranded RNA, a toll-like receptor 3 (TLR3) ligand and mimic of viral infection.Methods:To investigate the functional role of ORMDL3 in the poly I:C-induced inflammatory response in airway epithelial cells, ORMDL3 knockdown and over-expression models were established in human A549 epithelial cells and primary normal human bronchial epithelial (NHBE) cells. The cells were stimulated with poly I:C or the Th17 cytokine IL-17A. IL-6 and IL-8 levels in supernatants, mRNA levels of genes in the TLR3 pathway and inflammatory response from cell pellets were measured. ORMDL3 knockdown models in A549 and BEAS-2B epithelial cells were then infected with live human rhinovirus (HRV16) followed by IL-6 and IL-8 measurement.Results:ORMDL3 knockdown and over-expression had little influence on the transcript levels of TLR3 in airway epithelial cells. Time course studies showed that ORMDL3-deficient A549 and NHBE cells had an attenuated IL-6 and IL-8 response to poly I:C stimulation. A549 and NHBE cells over-expressing ORMDL3 released relatively more IL-6 and IL-8 following poly I:C stimulation. IL-17A exhibited a similar inflammatory response in ORMDL3 knockdown and over-expressing cells, but co-stimulation of poly I:C and IL-17A did not significantly enhance the IL-6 and IL-8 response. Transcript abundance of IFNB following poly I:C stimulation was not significantly altered by ORMDL3 knockdown or over-expression. Dampening of the IL-6 response by ORMDL3 knockdown was confirmed in HRV16 infected BEAS-2B and A549 cells.Conclusions:ORMDL3 regulates the viral inflammatory response in airway epithelial cells via mechanisms independent of the TLR3 pathway.
Ito K, Zhang Y, 2020, Fighting the common cold: ORMDL3 in the crosshairs?, American Journal of Respiratory Cell and Molecular Biology, Vol: 62, Pages: 676-677, ISSN: 1044-1549
Zuo X, Liu X, Chen C, et al., 2019, An in-depth analysis of glycosylated haemoglobin level, body mass index and left ventricular diastolic dysfunction in patients with type 2 diabetes, BMC Endocrine Disorders, Vol: 19, ISSN: 1472-6823
Background: Glycosylated hemoglobin (HbA1c) has a detrimental impact on the myocardium with left ventricular (LV) diastolic dysfunction. Obesity is a risk factor of type 2 diabetes. To understand the relationships between HbA1c, body mass index (BMI) and LV diastolic dysfunction, we performed this interaction analysis in patients with type 2 diabetes. Methods: Total 925 type 2 diabetes patients were selected from the patients who were diagnosed and treated at the First Affiliated Hospital of Shenzhen University. Patients’ BMI levels were defined as normal (BMI < 24kg/m2) and overweight /obese (BMI ≥ 24kg/m2). Patients’ HbA1c levels were grouped as HbA1c ≥ 9%、7% ≤ HbA1c < 9% and HbA1c < 7%. Logistic regression, stratified, interaction analyses, multivariate Cox regression and curve fitting analysis were performed to investigate the correlations and interactions between HbA1c and BMI with LV diastolic dysfunction. Results: The BMI levels were significantly associated with LV diastolic dysfunction in the patients with type 2 diabetes [adjusted model: 1.12 (1.05, 1.20), P = 0.001]. While HbA1c levels had association with LV diastolic dysfunction only in normal BMI group patients [adjusted model: 1.14 (1.01, 1.30), P = 0.0394] and curve correlation was observed. There was a significant interaction between BMI and HbA1c to affect LV diastolic dysfunction (P = 0.0335). Cox regression model analysis showed that the risk of LV diastolic dysfunction was a U type correlation with HbA1c levels in the normal weight group with turning point was HbA1c at 10%. HbA1c level was not found to have a significant association with LV diastolic dysfunction in overweight/obese group. Conclusions: In patients with type 2 diabetes, correlation between LV diastolic dysfunction and HbA1c was interactively affected by BMI. Glycemic control is beneficial to the heart function in normal body weight patients. For overweight/obese patients, the risk of LV diast
Zhang Y, Yan D, 2019, Personalized medicine of urate-lowering therapy for gout, Gout [Working Title], Editors: Kurose, Publisher: Intechopen, Pages: 1-23
Gout is a common and complex form of arthritis that is characterised with hyperuricaemia. It is required urate-lowering therapy (ULT) for lifelong management. ULT includes decreasing uric acid product in serum, increasing renal urate excretion and promoting uric acid to allantoin for excretion. Whole genome association studies in gout identified more than 40 genetic loci that influenced the serum uric acid levels. Most associated genes were found to affect renal urate excretion. Pharmacogenetics and pharmacogenomics approaches on ULT had revealed several genes that underlined the effectiveness and the adverse events of medications for gout. Together with the researches on epigenetic factors such as DNA methylations, miRNAs; and the discovery of environmental factors such as microbiota and metabolites, the current progress provides the opportunities for personalized management of ULT for treating hyperuricaemia and gout.
Zhang Y, Willis-Owen S, Spiegel S, et al., 2019, The ORMDL3 asthma gene regulates ICAM1 and has multiple effects on cellular inflammation, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 478-488, ISSN: 1073-449X
Rationale: Polymorphisms on chromosome 17q21 confer the major genetic susceptibility to childhood-onset asthma. Risk alleles positively correlate with ORMDL3 expression. The locus influences disease severity and the frequency of human rhinovirus (HRV) initiated exacerbations. ORMDL3 is known to regulate sphingolipid synthesis by binding serine palmitoyltransferase (SPT), but its role in inflammation is incompletely understood. Objectives: To investigate the role of ORMDL3 in cellular inflammation. Methods: We modelled time-series of IL1B-induced inflammation in A549 cells, using cytokine production as outputs and testing effects of ORMDL3 siRNA knockdown, ORMDL3 overexpression, and the SPT inhibitor myriocin. We replicated selected findings in normal human bronchial epithelial (NHBE) cells. Cytokine and metabolite levels were analysed by ANOVA. Transcript abundances were analysed by group means parameterisation, controlling the false discovery rate (FDR) below 0.05. Measurements and Main Results: Silencing ORMDL3 led to steroid-independent reduction of IL6 and IL8 release and reduced ER stress after IL1B. Overexpression and myriocin conversely augmented cytokine release. Knockdown reduced expression of genes regulating host-pathogen interactions, stress responses and ubiquitination: in particular ORMDL3 knockdown strongly reduced expression of the HRV receptor ICAM1. Silencing led to changes in levels of transcripts and metabolites integral to glycolysis. Increased levels of ceramides and the immune mediator sphingosine-1-P (S1P) were also observed. Conclusions: The results show ORMDL3 has pleiotropic effects during cellular inflammation, consistent with its substantial genetic influence on childhood asthma. Actions on ICAM1 provide a mechanism for the locus to confer susceptibility to HRV-induced asthma.
Liu Y, Zhang M, Lou L, et al., 2019, IRAK-1 M associates with susceptibility to adult-onset asthma and promotes chronic airway inflammation, Journal of Immunology, Vol: 202, Pages: 899-911, ISSN: 1550-6606
IL-1R–associated kinase (IRAK)-M regulates lung immunity during asthmatic airway inflammation. However, the regulatory effect of IRAK-M differs when airway inflammation persists. A positive association between IRAK-M polymorphisms with childhood asthma has been reported. In this study, we investigated the role of IRAK-M in the susceptibility to adult-onset asthma and in chronic airway inflammation using an animal model. Through genetic analysis of IRAK-M polymorphisms in a cohort of adult-onset asthma patients of Chinese Han ethnicity, we identified two IRAK-M single nucleotide polymorphisms, rs1624395 and rs1370128, genetically associated with adult-onset asthma. Functionally, the top-associated rs1624395, with an enhanced affinity to the transcription factor c-Jun, was associated with a higher expression of IRAK-M mRNA in blood monocytes. In contrast to the protective effect of IRAK-M in acute asthmatic inflammation, we found a provoking impact of IRAK-M on chronic asthmatic inflammation. Following chronic OVA stimulation, IRAK-M knockout (KO) mice presented with significantly less inflammatory cells, a lower Th2 cytokine level, a higher IFN-γ concentration, and increased percentage of Th1 cells in the lung tissue than wild type mice. Moreover, lung dendritic cells (DC) from OVA-treated IRAK-M KO mice expressed a higher percentage of costimulatory molecules PD-L1 and PD-L2. Mechanistically, in vitro TLR ligation led to a greater IFN-γ production by IRAK-M KO DCs than wild type DCs. These findings demonstrated a distinctive role of IRAK-M in maintaining chronic Th2 airway inflammation via inhibiting the DC-mediated Th1 activation and indicated a complex role for IRAK-M in the initiation and progression of experimental allergic asthma.
Yan D, Zhang Y, 2018, A response letter to allopurinol-induced toxic epidermal necrolysis and association with HLA-B*5801 in white patients, Pharmacogenetics and Genomics, Vol: 28, Pages: 268-269, ISSN: 1744-6872
Cheng H, Yan D, Zuo X, et al., 2018, A retrospective investigation of HLA-B*5801 in hyperuricemia patients in a Han population of China, Pharmacogenetics and Genomics, Vol: 28, Pages: 117-124, ISSN: 1744-6872
Hyperuricemia and gout have become increasingly prevalent in China. Allopurinol is an effective urate-lowering therapy but it has severe side-effects. HLA-B*5801 is highly associated with the allopurinol-induced toxic epidermal necrolysis and Stevens-Johnson syndrome. In this retrospective report, we had genotyped HLA-B*5801 in 253 cases of hyperuricemia and gout patients in a Han population in Shenzhen and analyzed the clinical management of medications. We found 30 carriers of HLA-B*5801 allele in 253 cases of hyperuricemia or gout patients in the population (11.9%). Allopurinol was prescribed in both HLA-B*5801 positive and negative groups. The evaluation of four models with or without genetic screening and management of allopurinol or febuxostat indicated the HLA-B*5801 screening had significant cost benefit for clinical management. HLA-B*5801 allele should be screened in all patients with hyperuiciemia and gout in the Chinese population.
Zhang Y, 2018, Gene expression during the activation of human B cells, Gene Expression and Regulation in Mammalian Cells - Transcription From General Aspects, Editors: Uchiumi, Rijeka, Croatia, Publisher: InTechOpen, ISBN: 978-953-51-3856-3
Human B lymphocytes not only play the critical role in the humoral immunity to generate antibodies, but also equally important to cellular immunity as B lymphocytes can present antigens to T lymphocytes and can release a range of potential immune-regulating cytokines after stimulations. Human immunoglobulin class switch recombination (CSR) in activated B cells is an essential process in the humoral immunity and the process is complicated and tightly controlled by many regulators. The recent genomic and genetic approaches in CSR identified novel genes that were actively involved in the process. Understanding the roles of the novel genes in CSR will bring new insights into the mechanisms of the process and new potential therapeutic targets for immunoglobulin-related disorders such as allergic asthma and autoimmune diseases.
, 2018, Gene Expression and Regulation in Mammalian Cells - Transcription From General Aspects, Publisher: InTech, ISBN: 9789535138556
Zhang Y, Poobalasingam T, Yates LL, et al., 2018, Manipulation of Dipeptidylpeptidase 10 in mouse and human in vivo and in vitro models indicates a protective role in asthma, Disease Models and Mechanisms, Vol: 11, ISSN: 1754-8403
We previously identified dipeptidylpeptidase 10 (DPP10) on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation in Dpp10 that caused an amino acid change from valine to aspartic acid in the β-propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established (Dpp10145D). Macroscopic examination and lung histology revealed no significant differences between wild-type and Dpp10145D/145D mice. However, after house dust mite (HDM) treatment, Dpp10 mutant mice showed significantly increased airway resistance in response to 100 mg/ml methacholine. Total serum IgE levels and bronchoalveolar lavage (BAL) eosinophil counts were significantly higher in homozygotes than in control mice after HDM treatment. DPP10 protein is present in airway epithelial cells and altered expression is observed in both tissue from asthmatic patients and in mice following HDM challenge. Moreover, knockdown of DPP10 in human airway epithelial cells results in altered cytokine responses. These results show that a Dpp10 point mutation leads to increased airway responsiveness following allergen challenge and provide biological evidence to support previous findings from human genetic studies.
Li Z, Zhang Y, 2017, Genetic and genomic approaches to pulmonary vascular diseases, Biomedical Genetics and Genomics, Vol: 2, ISSN: 2398-5399
Pulmonary vascular diseases include pulmonary arterial hypertension, pulmonary venous hypertension, pulmonary embolism and chronic thromboembolic disease. The mutations of BMPR2 were identified as major causes of primary pulmonary hypertension. The Factor V Leiden mutation is the most common genetic risk for pulmonary embolism. Candidate gene studies, genome-wide association studies, epigenetic studies, transcriptional profiling, miRNA profiling also identified novel causes for the diseases. Genetic and genomic approaches for pulmonary vascular disease provided new insights of the mechanisms and revealed the novel therapeutic targets. In this review, we summarise the current progress of genetic and genomic approaches for pulmonary vascular diseases and also discuss the future directions of the research for the diseases.
Zhang M, Lin S, Xiao W, et al., 2017, Applications of single-cell sequencing for human lung cancer: the progress and the future perspective, AIMS Biophysics, Vol: 4, Pages: 210-221, ISSN: 2377-9098
Human lung cancer is an extremely heterogeneous disease. Cell heterogeneity and diversity are responsible for lung cancer’s invasion, metastasis and the resistance to therapies. Recent developments of single-cell analysis make it possible for DNA sequencing, RNA sequencing and genomic element sequencing for single-cells from lung cancer. Methodology of single-cell sequencing was improved to reduce the errors in the processes due to applying tiny amount of the genetic materials. The single-cell sequencing for lung cancer has begun to reveal the deep insights of the cancer evolution and provided the new targets for clinical care. In this review, we briefly describe the methods of isolation, amplification and sequencing of single-cells. We also discuss the current progress in the research of lung cancer and the future prospects in single-cell analysis for the disease.
Zhang Y, Fear D, Willis-Owen S, et al., 2016, Global gene regulation during activation of immunoglobulin class switching in human B cells, Scientific Reports, Vol: 6, ISSN: 2045-2322
Immunoglobulin class switch recombination (CSR) to IgE is a tightly regulated process central to atopic disease. To profile the B-cell transcriptional responses underlying the activation of the germinal centre activities leading to the generation of IgE, naïve human B-cells were stimulated with IL-4 and anti-CD40. Gene expression and alternative splicing were profiled over 12 days using the Affymetrix Human Exon 1.0 ST Array. A total of 1,399 genes, forming 13 temporal profiles were differentially expressed. CCL22 and CCL17 were dramatically induced but followed a temporal trajectory distinct from classical mediators of isotype switching. AICDA, NFIL3, IRF4, XBP1 and BATF3 shared a profile with several genes involved in innate immunity, but with no recognised role in CSR. A transcription factor BHLHE40 was identified at the core of this profile. B-cell activation was also accompanied by variation in exon retention affecting >200 genes including CCL17. The data indicate a circadian component and central roles for the Th2 chemokines CCL22 and CCL17 in the activation of CSR.
Lin S, Zhang M, Zhang Y, 2016, The current genomic approaches for common respiratory diseases, Journal of Investigative Genomics, Vol: 3, Pages: 38-42, ISSN: 2373-4469
Common respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and lung cancer are increasing worldwide. Genomic approaches for the diseases provided new insights of the mechanisms and revealed the new therapeutic targets. Genome-wide association studies (GWAS), epigenetic studies, transcriptional profiling, RNA sequencing, chromatin immune precipitation (ChIP) sequencing and microbiota investigation make personalized medicine for common respiratory diseases possible in the near future. In this review, we summarize the current progress of genomic approaches for asthma, COPD and lung cancer and also discuss the future directions of the research of the diseases.
Löser S, Gregory LG, Zhang Y, et al., 2016, Pulmonary ORMDL3 is critical for induction of Alternaria induced allergic airways disease, Journal of Allergy and Clinical Immunology, Vol: 139, Pages: 1496-1507.e3, ISSN: 1097-6825
BACKGROUND: Genome-wide association studies have identified the ORMDL3 (ORM (yeast)-like protein isoform 3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. OBJECTIVE: We sought to investigate in vivo the functional role of ORMDL3 in disease inception. METHODS: An Ormdl3 deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata determined. An adeno-associated viral vector was also utilized to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 KO mice. RESULTS: Ormdl3 knock-out mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response and ORMDL3 was found to play a critical role in driving the ATF6 mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum-associated degradation pathway. Additionally ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen-induced allergic airways disease. CONCLUSIONS: This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses.
Zhang Y, Dean C, Loeser S, et al., 2016, Systematic dissection of ORMDL3 function in vitro and in vivo, ERS International Congress 2016, Publisher: European Respiratory Society, ISSN: 0903-1936
ORMDL3 on human chromosome 17q21 is a major genetic influence for childhood asthma, severe asthma and asthma exacerbations. To understand further the functional roles of ORMDL3, we established both human airway epithelial models and a recombineering-generated murine Ormdl3 knockout model. The influences of ORMDL3 on inflammatory responses in vitro and in vivo were investigated.We performed gene silencing using siRNA for two days in airway epithelium cells (A549, Beas2B and NHBE cells) after which cells were stimulated with IL1B. ORMDL3 knockdown-epithelial cells released much less IL6 and IL8 at 10 hours after stimulation (P < 0.01 respectively). Over-expression of ORMDL3 in epithelial cells resulted in a significant increase in release of IL6 and IL8 shortly after stimulation. Serine-palmitoyl transferase (SPT) is the key enzyme of sphingolipid metabolism. Treatment of epithelial cells with the SPT inhibitor myriocin resulted in an increase in release of IL6 and IL8 after stimulation, mirroring the results seen with the overexpression model. A systemic metabolic screening of the ORMDL3 knockdown epithelial cells revealed ORMDL3 to be involved not only in regulating sphingolipid metabolism but also lysophospholipids metabolism and the regulation of glycolysis. Parallel global gene expression profiling of the same cells identified key transcripts involved in regulating the inflammatory response. The lung function of Ormdl3 knockout mice also exhibited a reduced response after Alternaria alternata challenge.Our findings indicate ORMDL3 is a key molecule involved in the regulation of the inflammation response through multiple pathways and is a potential therapeutic target for asthma.
Zhang Y, 2016, Potential therapeutic targets from genetic and epigenetic approaches for asthma, World Journal of Translational Medicine, Vol: 5, Pages: 14-25, ISSN: 2220-6132
Asthma is a complex disorder characterised by inflammation of airway and symptoms of wheeze and shortness of breath. Allergic asthma, atopic dermatitis and allergic rhinitis are immunoglobulin E (IgE) related diseases. Current therapies targeting asthma rely on non-specific medication to control airway inflammation and prevent symptoms. Severe asthma remains difficult to treat. Genetic and genomic approaches of asthma and IgE identified many novel loci underling the disease pathophysiology. Recent epigenetic approaches also revealed the insights of DNA methylation and chromatin modification on histones in asthma and IgE. More than 30 miRNAs have been identified to have regulation roles in asthma. Understanding the pathways of the novel genetic loci and epigenetic elements in asthma and IgE will provide new therapeutic means for clinical management of the disease in future.
Holt RJ, Vandiedonck C, Willis-Owen SA, et al., 2015, A functional AT/G polymorphism in the 5'-untranslated region (UTR) of SETDB2 in the IgE locus on human chromosome 13q14, Genes and Immunity, Vol: 16, Pages: 488-494, ISSN: 1476-5470
The IgE associated locus on human chromosome 13q14 influencing asthma related traits contains the genes PHF11 and SETDB2. SETDB2 is located in the same linkage disequilibrium region as PHF11 and polymorphisms within SETDB2 have been shown to associate with total serum IgE levels. In this report, we sequenced the 15 exons of SETDB2 and identified a single previously un-genotyped mutation (AT/G, rs386770867) in the 5’ untranslated region (UTR) of the gene. The polymorphism was found to be significantly associated with serum IgE levels in our asthma cohort (P = 0.0012). Electrophoretic mobility shift assays (EMSA) revealed that the transcription factor YY1 binds to the AT allele whilst SRY binds to the G allele. Allele-specific transcription analysis (allelotyping) was performed in 35 individuals heterozygous for rs386770867 from a panel of 200 British families ascertained through probands with severe Stage 3 asthma. The AT allele was found to be significantly over expressed in these individuals (P = 1.26 x 10-21). A dual luciferase assay with the pGL3 Luciferase report gene showed that the AT allele significantly affects transcriptional activities. Our results indicate the IgE-associated AT/G polymorphism (rs386770867) regulates transcription of SETDB2.
Yun Zhang YZ, 2015, Functional Dissection of Novel Genes on Complicated Diseases, Journal of Genetic Syndromes & Gene Therapy, Vol: 06
Loeser S, Zhang Y, Gregory L, et al., 2014, Novel insights into the in vivo function of Ormdl3 - a gene associated with the onset of childhood asthma, IMMUNOLOGY, Vol: 143, Pages: 59-59, ISSN: 0019-2805
Zhang Y, Dean C, Chessum L, et al., 2014, Functional analysis of a novel ENU-induced PHD finger 11 (Phf11) mouse mutant, MAMMALIAN GENOME, Vol: 25, Pages: 573-582, ISSN: 0938-8990
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