Revealing the acute asthma ignorome: characterization and validation of uninvestigated gene networks

Systems biology provides opportunities to fully understand the genes and pathways in disease pathogenesis. We used literature knowledge and unbiased multiple data meta-analysis paradigms to analyze microarray datasets across different mouse strains and acute allergic asthma models. Our combined gene-driven and pathway-driven strategies generated a stringent signature list totaling 933 genes with 41% (440) asthma-annotated genes and 59% (493) ignorome genes, not previously associated with asthma. Within the list, we identified inflammation, circadian rhythm, lung-specific insult response, stem cell proliferation domains, hubs, peripheral genes, and super-connectors that link the biological domains (Il6, Il1ß, Cd4, Cd44, Stat1, Traf6, Rela, Cadm1, Nr3c1, Prkcd, Vwf, Erbb2). In conclusion, this novel bioinformatics approach will be a powerful strategy for clinical and across species data analysis that allows for the validation of experimental models and might lead to the discovery of novel mechanistic insights in asthma.

[1]  C. Irvin,et al.  Animal Models of Allergic Airways Disease: Where Are We and Where to Next? , 2014, Journal of cellular biochemistry.

[2]  Carolina Gutierrez,et al.  HER2: biology, detection, and clinical implications. , 2011, Archives of pathology & laboratory medicine.

[3]  Andrew I Su,et al.  Power-law-like distributions in biomedical publications and research funding , 2007, Genome Biology.

[4]  L. Ivashkiv,et al.  Inhibition of IFN-gamma signaling by glucocorticoids. , 2003, Journal of immunology.

[5]  C. Scheiermann,et al.  Circadian control of the immune system , 2013, Nature Reviews Immunology.

[6]  T. Nagato,et al.  Expression and functional role of MDL‐1 (CLEC5A) in mouse myeloid lineage cells , 2009, Journal of leukocyte biology.

[7]  Bill Bynum,et al.  Lancet , 2015, The Lancet.

[8]  P. Finn,et al.  Molecular Systems Biology 3; Article number 98; doi:10.1038/msb4100138 Citation: Molecular Systems Biology 3:98 , 2022 .

[9]  G. Peltz,et al.  Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma , 2000, Nature Immunology.

[10]  A. Blann,et al.  High dose dexamethasone increases circulating P-selectin and von Willebrand factor levels in healthy men , 2005, Thrombosis and Haemostasis.

[11]  P. O'Byrne,et al.  Allergen-induced increases in IL-5 receptor alpha-subunit expression on bone marrow-derived CD34+ cells from asthmatic subjects. A novel marker of progenitor cell commitment towards eosinophilic differentiation. , 1997, The Journal of clinical investigation.

[12]  T. Chatila,et al.  Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma , 2009, The Journal of experimental medicine.

[13]  Michael H Smolensky,et al.  Chronobiology and chronotherapy of allergic rhinitis and bronchial asthma. , 2007, Advanced drug delivery reviews.

[14]  Achsah D. Keegan,et al.  Interleukin-4 and Interleukin-13 Signaling Connections Maps , 2003, Science.

[15]  Ramin Homayouni,et al.  Functionally Enigmatic Genes: A Case Study of the Brain Ignorome , 2014, PloS one.

[16]  Robert Hoffmann,et al.  Temporal patterns of genes in scientific publications , 2007, Proceedings of the National Academy of Sciences.

[17]  G. Peluso,et al.  Phenotypic features of alveolar monocytes/macrophages and IL‐8 gene activation by IL‐1 and TNF‐α in asthmatic patients , 2000, Allergy.

[18]  David Tat-Wei Tan,et al.  CLEC5A Regulates Japanese Encephalitis Virus-Induced Neuroinflammation and Lethality , 2012, PLoS pathogens.

[19]  P. O'Byrne,et al.  Sputum CD34+IL-5Ralpha+ cells increase after allergen: evidence for in situ eosinophilopoiesis. , 2004, American journal of respiratory and critical care medicine.

[20]  C. Denis,et al.  Blocking von Willebrand factor for treatment of cutaneous inflammation. , 2014, The Journal of investigative dermatology.

[21]  J. Samet,et al.  Murine Lung Responses to Ambient Particulate Matter: Genomic Analysis and Influence on Airway Hyperresponsiveness , 2008, Environmental health perspectives.

[22]  New asthma biomarkers: lessons from murine models of acute and chronic asthma. , 2009, American journal of physiology. Lung cellular and molecular physiology.

[23]  Q. Hamid,et al.  Role of transforming growth factor-β in airway remodeling in asthma. , 2011, American journal of respiratory cell and molecular biology.

[24]  Paolo Sassone-Corsi,et al.  Circadian clock proteins and immunity. , 2014, Immunity.

[25]  Nikolaos M. Nikolaidis,et al.  Transcript Signatures in Experimental Asthma: Identification of STAT6-Dependent and -Independent Pathways1 , 2004, The Journal of Immunology.

[26]  Chi-Huey Wong,et al.  CLEC5A is critical for dengue-virus-induced lethal disease , 2008, Nature.

[27]  D. Tumes,et al.  Expression of survivin in lung eosinophils is associated with pathology in a mouse model of allergic asthma. , 2009, International immunology.

[28]  Amy E. Baek,et al.  Ovalbumin sensitization and challenge increases the number of lung cells possessing a mesenchymal stromal cell phenotype , 2010, Respiratory research.

[29]  Qutayba Hamid,et al.  Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. , 2003, The Journal of clinical investigation.

[30]  H. Daniel,et al.  The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology , 2004, Pflügers Archiv.

[31]  Z. Szallasi,et al.  Reliability and reproducibility issues in DNA microarray measurements. , 2006, Trends in genetics : TIG.

[32]  S. Sealfon,et al.  Validated Genomic Approach to Study Differentially Expressed Genes in Complex Tissues , 2002, Neurochemical Research.

[33]  P. O'Byrne,et al.  Sputum CD34+IL-5Rα+Cells Increase after Allergen: Evidence forIn SituEosinophilopoiesis , 2004 .

[34]  Alfonso Valencia,et al.  Life cycles of successful genes. , 2003, Trends in genetics : TIG.

[35]  J. Banchereau,et al.  CD40L activation of dendritic cells down-regulates DORA, a novel member of the immunoglobulin superfamily. , 1998, Molecular immunology.

[36]  Nikolaos M. Nikolaidis,et al.  Expression and regulation of a disintegrin and metalloproteinase (ADAM) 8 in experimental asthma. , 2004, American journal of respiratory cell and molecular biology.

[37]  Krishna R. Kalari,et al.  Human glucocorticoid receptor alpha gene (NR3C1) pharmacogenomics: gene resequencing and functional genomics. , 2009, The Journal of clinical endocrinology and metabolism.

[38]  S. Steinberg.  Distinctive activation mechanisms and functions for protein kinase Cdelta. , 2004, The Biochemical journal.

[39]  G. Lip,et al.  Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers. , 2006, Thrombosis research.

[40]  Qing Zhao,et al.  TRAF6 Inhibition Rescues Dexamethasone-Induced Muscle Atrophy , 2014, International journal of molecular sciences.

[41]  A. Falus,et al.  Gene expression profiling of experimental asthma reveals a possible role of paraoxonase-1 in the disease. , 2009, International immunology.

[42]  T. Hudson,et al.  Modulation of the allergic asthma transcriptome following resiquimod treatment. , 2009, Physiological genomics.

[43]  L. Ivashkiv,et al.  Inhibition of IFN-γ Signaling by Glucocorticoids1 , 2003, The Journal of Immunology.

[44]  S. Hester,et al.  Increased transcription of immune and metabolic pathways in naive and allergic mice exposed to diesel exhaust. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[45]  Nir Friedman,et al.  A functional and regulatory map of asthma. , 2008, American journal of respiratory cell and molecular biology.

[46]  E. Stupka.  The emergence of genomics in mouse asthma models , 2009 .

[47]  P. Bradding,et al.  CADM1 Is a Key Receptor Mediating Human Mast Cell Adhesion to Human Lung Fibroblasts and Airway Smooth Muscle Cells , 2013, PloS one.

[48]  Eric P Hoffman,et al.  Delineation of a Gene Network Underlying the Pulmonary Response to Oxidative Stress in Asthma , 2009, Journal of Investigative Medicine.

[49]  Monica Kraft,et al.  IL-13 in asthma and allergic disease: asthma phenotypes and targeted therapies. , 2012, The Journal of allergy and clinical immunology.