Multi–omic analysis of signalling factors in inflammatory comorbidities

BackgroundInflammation is a core element of many different, systemic and chronic diseases that usually involve an important autoimmune component. The clinical phase of inflammatory diseases is often the culmination of a long series of pathologic events that started years before. The systemic characteristics and related mechanisms could be investigated through the multi–omic comparative analysis of many inflammatory diseases. Therefore, it is important to use molecular data to study the genesis of the diseases. Here we propose a new methodology to study the relationships between inflammatory diseases and signalling molecules whose dysregulation at molecular levels could lead to systemic pathological events observed in inflammatory diseases.ResultsWe first perform an exploratory analysis of gene expression data of a number of diseases that involve a strong inflammatory component. The comparison of gene expression between disease and healthy samples reveals the importance of members of gene families coding for signalling factors. Next, we focus on interested signalling gene families and a subset of inflammation related diseases with multi–omic features including both gene expression and DNA methylation. We introduce a phylogenetic–based multi–omic method to study the relationships between multi–omic features of inflammation related diseases by integrating gene expression, DNA methylation through sequence based phylogeny of the signalling gene families. The models of adaptations between gene expression and DNA methylation can be inferred from pre–estimated evolutionary relationship of a gene family. Members of the gene family whose expression or methylation levels significantly deviate from the model are considered as the potential disease associated genes.ConclusionsApplying the methodology to four gene families (the chemokine receptor family, the TNF receptor family, the TGF– β gene family, the IL–17 gene family) in nine inflammation related diseases, we identify disease associated genes which exhibit significant dysregulation in gene expression or DNA methylation in the inflammation related diseases, which provides clues for functional associations between the diseases.

[1]  Yan V. Sun,et al.  Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases. , 2016, Advances in genetics.

[2]  Olle Korsgren,et al.  A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets. , 2012, Cell metabolism.

[3]  B. Ahmer,et al.  The commensal microbiota exacerbate infectious colitis in stressor-exposed mice , 2016, Brain, Behavior, and Immunity.

[4]  Santo Fortunato,et al.  Detection of gene communities in multi-networks reveals cancer drivers , 2015, Scientific Reports.

[5]  M. Mihailović,et al.  The Importance of the CXCL12/CXCR4 Axis in Therapeutic Approaches to Diabetes Mellitus Attenuation , 2015, Front. Immunol..

[6]  Peter Devilee,et al.  Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma , 2006, BMC Medical Genetics.

[7]  Tanja Stadler,et al.  Parallel Likelihood Calculation for Phylogenetic Comparative Models: the SPLITT C++ Library , 2017, bioRxiv.

[8]  A. Mogi,et al.  Colitis mimicking graft-versus-host disease during treatment with the anti-CCR4 monoclonal antibody, mogamulizumab , 2015, International Journal of Hematology.

[9]  A. IJzerman,et al.  Bias in chemokine receptor signalling. , 2014, Trends in immunology.

[10]  Pietro Liò,et al.  Systems medicine of inflammaging , 2015, Briefings Bioinform..

[11]  S. Lira,et al.  Requirement for the Chemokine Receptor Ccr6 in Allergic Pulmonary Inflammation , 2001, The Journal of experimental medicine.

[12]  N. Eldredge,et al.  Punctuated equilibrium comes of age , 1993, Nature.

[13]  B. Stecher The Roles of Inflammation, Nutrient Availability and the Commensal Microbiota in Enteric Pathogen Infection , 2015, Microbiology spectrum.

[14]  G. Corazza,et al.  The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis , 2013, Fibrogenesis & tissue repair.

[15]  Y. Kudva,et al.  Successful disease-specific induced pluripotent stem cell generation from patients with kidney transplantation , 2011, Stem Cell Research & Therapy.

[16]  A. Richmond,et al.  Chemokines and chemokine receptors: new insights into cancer-related inflammation. , 2010, Trends in molecular medicine.

[17]  C. Benoist,et al.  Deficiency of CXCR2, but not other chemokine receptors, attenuates autoantibody-mediated arthritis in a murine model. , 2010, Arthritis and rheumatism.

[18]  E. Grant,et al.  Pharmacological targeting reveals distinct roles for CXCR2/CXCR1 and CCR2 in a mouse model of arthritis. , 2010, Biochemical and biophysical research communications.

[19]  F. Luyten,et al.  Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis. , 2003, Arthritis and rheumatism.

[20]  E. Matteson,et al.  An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis , 2016, Genome Medicine.

[21]  Dan Wang,et al.  Integrating genomic, epigenomic, and transcriptomic features reveals modular signatures underlying poor prognosis in ovarian cancer. , 2013, Cell reports.

[22]  T. Mcclanahan,et al.  Involvement of chemokine receptors in breast cancer metastasis , 2001, Nature.

[23]  A. Lusis,et al.  Considerations for the design of omics studies , 2017 .

[24]  Tudor I. Oprea,et al.  Temporal disease trajectories condensed from population-wide registry data covering 6.2 million patients , 2014, Nature Communications.

[25]  F. Balkwill,et al.  Inflammation and cancer: advances and new agents , 2015, Nature Reviews Clinical Oncology.

[26]  M. Endres,et al.  Chondrogenic differentiation of human subchondral progenitor cells is impaired by rheumatoid arthritis synovial fluid , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[27]  S. Itoh,et al.  Implication of TGF-β as a survival factor during tumour development. , 2012, Journal of biochemistry.

[28]  C. Cho,et al.  Change in the Gastro-Intestinal Tract by Overexpressed Activin Beta A , 2015, Molecules and cells.

[29]  J. Felsenstein Maximum-likelihood estimation of evolutionary trees from continuous characters. , 1973, American journal of human genetics.

[30]  Yu-Mei Li,et al.  mRNA expression of chemokine receptors on peripheral blood mononuclear cells and correlation with clinical features in systemic lupus erythematosus patients. , 2010, Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih.

[31]  M Rudemo,et al.  A network-based analysis of allergen-challenged CD4+ T cells from patients with allergic rhinitis , 2006, Genes and Immunity.

[32]  Peter A. Jones Functions of DNA methylation: islands, start sites, gene bodies and beyond , 2012, Nature Reviews Genetics.

[33]  C. Traidl‐Hoffmann,et al.  CD27 expression on allergen-specific T cells: a new surrogate for successful allergen-specific immunotherapy? , 2012, Journal of Allergy and Clinical Immunology.

[34]  Weixu Chen,et al.  Enteric microbiota leads to new therapeutic strategies for ulcerative colitis. , 2014, World journal of gastroenterology.

[35]  B. Han,et al.  Open Access Research Article Copy Number Variation at Leptin Receptor Gene Locus Associated with Metabolic Traits and the Risk of Type 2 Diabetes Mellitus , 2022 .

[36]  Jeroen Krijgsveld,et al.  Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis , 2015 .

[37]  R. Xavier,et al.  Role of tumor necrosis factor receptor 2 (TNFR2) in colonic epithelial hyperplasia and chronic intestinal inflammation in mice. , 2002, Gastroenterology.

[38]  R. Tibshirani,et al.  Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins , 2007, Nature Medicine.

[39]  C. Fox,et al.  Efficient Recycled Algorithms for Quantitative Trait Models on Phylogenies , 2015, Genome biology and evolution.

[40]  P. Ghadjar,et al.  Changes in CXCL12/CXCR4-chemokine expression during onset of colorectal malignancies , 2011, Tumor Biology.

[41]  Kristiina Aittomäki,et al.  Recessively inherited right atrial isomerism caused by mutations in growth/differentiation factor 1 (GDF1). , 2010, Human molecular genetics.

[42]  M. Diculescu,et al.  Recent insights into the molecular pathogenesis of Crohn’s disease: a review of emerging therapeutic targets , 2016, Clinical and experimental gastroenterology.

[43]  K. Bartoszek,et al.  A novel algorithm to reconstruct phylogenies using gene sequences and expression data , 2014, BIOINFORMATICS 2014.

[44]  Gerhard A Müller,et al.  Decrease in expression of bone morphogenetic proteins 4 and 5 in synovial tissue of patients with osteoarthritis and rheumatoid arthritis , 2006, Arthritis research & therapy.

[45]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[46]  Rasmus Nielsen,et al.  Modeling gene expression evolution with an extended Ornstein-Uhlenbeck process accounting for within-species variation. , 2014, Molecular biology and evolution.

[47]  A. King,et al.  Phylogenetic Comparative Analysis: A Modeling Approach for Adaptive Evolution , 2004, The American Naturalist.

[48]  David A. Knowles,et al.  Distinct Epigenomic Features in End-Stage Failing Human Hearts , 2011, Circulation.

[49]  J. Gisbert,et al.  Role of TNFRSF1B polymorphisms in the response of Crohn's disease patients to infliximab. , 2014, Human immunology.

[50]  J. Chirgwin,et al.  Hypoxia and TGF-β Drive Breast Cancer Bone Metastases through Parallel Signaling Pathways in Tumor Cells and the Bone Microenvironment , 2009, PloS one.

[51]  P. Lio’,et al.  The landscape of DNA repeat elements in human heart failure , 2012, Genome Biology.

[52]  Krin A. Kay,et al.  The implications of human metabolic network topology for disease comorbidity , 2008, Proceedings of the National Academy of Sciences.

[53]  Eric W Goolsby,et al.  Rapid maximum likelihood ancestral state reconstruction of continuous characters: A rerooting‐free algorithm , 2017, Ecology and evolution.

[54]  T. Schall,et al.  Overcoming hurdles in developing successful drugs targeting chemokine receptors , 2011, Nature Reviews Immunology.

[55]  Kumardeep Chaudhary,et al.  Deep Learning–Based Multi-Omics Integration Robustly Predicts Survival in Liver Cancer , 2017, Clinical Cancer Research.

[56]  M. Sisto,et al.  Downstream activation of NF‐κB in the EDA‐A1/EDAR signalling in Sjögren's syndrome and its regulation by the ubiquitin‐editing enzyme A20 , 2016, Clinical and experimental immunology.

[57]  J. Silvestre,et al.  Diabetes Mellitus and Ischemic DiseasesSignificance , 2014 .

[58]  J. Trygg,et al.  Metabolite and Lipid Profiling of Biobank Plasma Samples Collected Prior to Onset of Rheumatoid Arthritis , 2016, PloS one.

[59]  J. Faith,et al.  Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinal immune responses , 2016, The Journal of experimental medicine.

[60]  H. Matsumoto,et al.  Primary colorectal lymphoma comprising both components of diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma combined with cytomegalovirus colitis , 2016, Clinical Journal of Gastroenterology.

[61]  F. Ginhoux,et al.  Crucial roles of XCR1-expressing dendritic cells and the XCR1-XCL1 chemokine axis in intestinal immune homeostasis , 2016, Scientific Reports.

[62]  Yitao Wang,et al.  American Ginseng Attenuates Colitis-Associated Colon Carcinogenesis in Mice: Impact on Gut Microbiota and Metabolomics , 2016, Cancer Prevention Research.

[63]  A. Krolewski,et al.  Circulating TGF-β1–Regulated miRNAs and the Risk of Rapid Progression to ESRD in Type 1 Diabetes , 2015, Diabetes.

[64]  J. Silvestre,et al.  Diabetes Mellitus and Ischemic Diseases: Molecular Mechanisms of Vascular Repair Dysfunction , 2014, Arteriosclerosis, thrombosis, and vascular biology.

[65]  J. Borst,et al.  Blocking CD27-CD70 Costimulatory Pathway Suppresses Experimental Colitis1 , 2009, The Journal of Immunology.

[66]  Thomas B. Kepler,et al.  Th17 cytokines differentiate obesity from obesity-associated type 2 diabetes and promote TNFα production , 2015, Obesity.

[67]  Thomas Lengauer,et al.  A new measure for functional similarity of gene products based on Gene Ontology , 2006, BMC Bioinformatics.

[68]  J. Suvisaari,et al.  Assessment of the Neuropeptide S System in Anxiety Disorders , 2010, Biological Psychiatry.

[69]  R. Jia,et al.  Transcriptome Analysis and Identification of Differentially Expressed Transcripts of Immune-Related Genes in Spleen of Gosling and Adult Goose , 2015, International journal of molecular sciences.

[70]  T. Mcclanahan,et al.  TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology , 2007, Nature Immunology.

[71]  K. Natarajan,et al.  High glucose driven expression of pro-inflammatory cytokine and chemokine genes in lymphocytes: molecular mechanisms of IL-17 family gene expression. , 2014, Cellular signalling.

[72]  D. Staines,et al.  Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients , 2015, Journal of Translational Medicine.

[73]  ShiHong Wen,et al.  TGF‐β1 improves mucosal IgA dysfunction and dysbiosis following intestinal ischaemia–reperfusion in mice , 2016, Journal of cellular and molecular medicine.

[74]  Xiaojing Ma,et al.  A novel crosstalk between TLR4- and NOD2-mediated signaling in the regulation of intestinal inflammation , 2015, Scientific Reports.

[75]  R. Pong-Wong,et al.  Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep. , 2009, Reproduction.

[76]  M. Maes,et al.  Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut–brain pathways , 2015, CNS Spectrums.

[77]  A. Regev,et al.  Induction and molecular signature of pathogenic TH17 cells , 2012, Nature Immunology.

[78]  T. Guise,et al.  TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases , 2011, Cancer Microenvironment.

[79]  J. Vendrell,et al.  TWEAK: A New Player in Obesity and Diabetes , 2013, Front. Immunol..

[80]  E. El-Omar,et al.  Role of the gut microbiota in inflammatory bowel disease pathogenesis: what have we learnt in the past 10 years? , 2014, World journal of gastroenterology.

[81]  K. Mori,et al.  Cloning of follistatin-related protein as a novel autoantigen in systemic rheumatic diseases. , 1998, International immunology.

[82]  S. Manicassamy,et al.  CXCR2 knockout mice are protected against DSS-colitis-induced acute kidney injury and inflammation. , 2013, American journal of physiology. Renal physiology.

[83]  R. Kambadur,et al.  Myostatin Induces Insulin Resistance via Casitas B-Lineage Lymphoma b (Cblb)-mediated Degradation of Insulin Receptor Substrate 1 (IRS1) Protein in Response to High Calorie Diet Intake* , 2014, The Journal of Biological Chemistry.

[84]  G. Merceron,et al.  mvmorph: an r package for fitting multivariate evolutionary models to morphometric data , 2015 .

[85]  C. Nguyen,et al.  Integrative analysis of the transcriptome profiles observed in type 1, type 2 and gestational diabetes mellitus reveals the role of inflammation , 2014, BMC Medical Genomics.

[86]  Y. Bao,et al.  Association of Genetic Variants of BMP4 with Type 2 Diabetes Mellitus and Clinical Traits in a Chinese Han Population , 2013, BioMed research international.

[87]  C. Ané,et al.  A linear-time algorithm for Gaussian and non-Gaussian trait evolution models. , 2014, Systematic biology.

[88]  F. Laenger,et al.  Growth differentiation factor-15 in idiopathic pulmonary arterial hypertension. , 2008, American journal of respiratory and critical care medicine.

[89]  A. Stadnyk,et al.  Local chemerin levels are positively associated with DSS-induced colitis but constitutive loss of CMKLR1 does not protect against development of colitis , 2015, Physiological reports.

[90]  R. J. Hocking,et al.  TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. , 2006, Immunity.

[91]  Tao You,et al.  Association of growth/differentiation factor 1 gene polymorphisms with the risk of congenital heart disease in the Chinese Han population , 2012, Molecular Biology Reports.

[92]  R. Tersigni,et al.  TGF‐β1 production in inflammatory bowel disease: differing production patterns in Crohn's disease and ulcerative colitis , 2003 .

[93]  C. Deng,et al.  TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation , 2012, International journal of biological sciences.

[94]  Zhijun Xie,et al.  Alterations of the gut microbiome in Chinese patients with systemic lupus erythematosus , 2016, Gut Pathogens.

[95]  Gerard C Blobe,et al.  Role of transforming growth factor-beta superfamily signaling pathways in human disease. , 2008, Biochimica et biophysica acta.

[96]  Y. Benjamini,et al.  THE CONTROL OF THE FALSE DISCOVERY RATE IN MULTIPLE TESTING UNDER DEPENDENCY , 2001 .

[97]  Mark C. Coles,et al.  Tyrosine kinase receptor RET is a key regulator of Peyer’s Patch organogenesis , 2007, Nature.

[98]  T. Wilhelm,et al.  Constitutive upregulation of the transforming growth factor-β pathway in rheumatoid arthritis synovial fibroblasts , 2007, Arthritis research & therapy.

[99]  K. Hur Is GDF15 a Novel Biomarker to Predict the Development of Prediabetes or Diabetes? , 2014, Diabetes & metabolism journal.

[100]  J. Fernández-Real,et al.  Expression of TWEAK and its receptor Fn14 in human subcutaneous adipose tissue. Relationship with other inflammatory cytokines in obesity. , 2006, Cytokine.

[101]  D. Hartl,et al.  Optimization of gene expression by natural selection , 2009, Proceedings of the National Academy of Sciences.

[102]  C. Shaw,et al.  Activin signaling: effects on body composition and mitochondrial energy metabolism. , 2009, Endocrinology.

[103]  T. F. Hansen,et al.  A Comparative Method for Studying Adaptation to a Randomly Evolving Environment , 2008, Evolution; international journal of organic evolution.

[104]  Terry M. Therneau,et al.  What Does PLIER Really Do? , 2008, Cancer informatics.

[105]  C. Shun,et al.  Prevention of Colitis and Colitis-Associated Colorectal Cancer by a Novel Polypharmacological Histone Deacetylase Inhibitor , 2016, Clinical Cancer Research.

[106]  M. Sułkowska,et al.  Relations of TGF‐beta1 with HIF‐1alpha, GLUT‐1 and longer survival of colorectal cancer patients , 2009, Pathology.

[107]  G. Zhu,et al.  RELT, a new member of the tumor necrosis factor receptor superfamily, is selectively expressed in hematopoietic tissues and activates transcription factor NF-kappaB. , 2001, Blood.

[108]  B. O’Meara,et al.  MODELING STABILIZING SELECTION: EXPANDING THE ORNSTEIN–UHLENBECK MODEL OF ADAPTIVE EVOLUTION , 2012, Evolution; international journal of organic evolution.

[109]  A. M. Orgueira Hidden among the crowd: differential DNA methylation-expression correlations in cancer occur at important oncogenic pathways , 2015, Front. Genet..

[110]  T. F. Hansen,et al.  Interpreting the evolutionary regression: the interplay between observational and biological errors in phylogenetic comparative studies. , 2012, Systematic biology.

[111]  F. Balkwill Cancer and the chemokine network , 2004, Nature Reviews Cancer.

[112]  P. Tighe,et al.  Differential expression of TGF-beta isoforms by normal and inflammatory bowel disease intestinal myofibroblasts. , 2002, American journal of physiology. Cell physiology.

[113]  J. Reeves,et al.  Circulating Concentrations of Growth Differentiation Factor 11 Are Heritable and Correlate With Life Span. , 2016, The journals of gerontology. Series A, Biological sciences and medical sciences.

[114]  T. F. Hansen STABILIZING SELECTION AND THE COMPARATIVE ANALYSIS OF ADAPTATION , 1997, Evolution; international journal of organic evolution.

[115]  H. Kipen,et al.  Suppression of the NF-κB Pathway by Diesel Exhaust Particles Impairs Human Antimycobacterial Immunity , 2012, The Journal of Immunology.

[116]  T. F. Hansen,et al.  A phylogenetic comparative method for studying multivariate adaptation. , 2012, Journal of theoretical biology.

[117]  P. Emery,et al.  Review: Preclinical Rheumatoid Arthritis: Progress Toward Prevention , 2016, Arthritis & rheumatology.