Meta-analysis of irradiated white blood cells gene expression for biodosimetry marker detection

VANESA BIOLATTI; NICOLAS BELLORA; IRENE LAURA IBAÑEZ

Buenos Aires

Simposio; Argentine Symposium of Young Bioinformatics Researchers 2 (1SAJIB); 2017

ISCB RSG-Argentina

H4 { margin-bottom: 0.08in; direction: ltr; color: rgb(0, 0, 0); }H4.western { font-family: "Liberation Sans",serif; font-size: 14pt; font-weight: normal; }H4.cjk { font-family: "Liberation Sans"; font-size: 14pt; font-weight: normal; }H4.ctl { font-family: "Liberation Sans"; font-size: 14pt; font-weight: normal; }P { margin-bottom: 0.1in; line-height: 120%; }Meta-analysis ofirradiated white blood cells gene expression for biodosimetry markerdetectionOBJECTIVES:The analysis of geneexpression in blood cells has been emerged as a novel method forbiodosimetry marker detection. The differentially expressed genescould predict the clinical outcome of patients and guide theprevention, early diagnosis and treatment of ionizing radiationinduced damage, improving traditional approaches. The aim of thisstudy was to identify recurrent de-regulated genes which could beproposed as biomarkers to characterize ionizing radiation exposure.In order to achieve this goal, a meta-analysis of microarrayexpression data of irradiated blood cells at 2 Gy and 24 hpost-exposure was performed.METHODS:Dataof four expression microarrays obtained from Gene Expression Omnibus(GEO) were evaluated by using the R programming language andBioconductor packages. Differentially expressed genes (DEGs) werescreened by Limma package (parameters: lfc=1 and p<0.05). Thefunctional classification was performedwith the Database for Annotation, Visualization and IntegratedDiscovery (DAVID). The molecular signatures database (MSigDB) wasutilized to test for enrichment of DEGs.  Potentialtranscription factors (TFs) as master regulators of key DEGs werepredicted using iRegulon plugin and functional interactions were doneusing GeneMANIA and Cytoscape.RESULTS:Seven upregulated(E2F7, PLK2, DRAM1, POLR2A, NUDT15, C12orf15 and GADD45A) and twodownregulated (TCF4 and HRK) genes were identified (lfc>0.5 andp<0.05) for further validation using quantitative PCR. TheGene Ontology enrichment analysis revealed that themost significantly enriched terms within the DEGs were:regulation after exposure to ionizing radiation, p53pathway, cell cycle checkpoint involved in G1/S transition, cellcycle arrest and processes induced by the detection of DNAdamage. Besides, based on a motif discovery method & ChIPseqenrichment, performed by iRegulon, E2F7 and TCF4 were detected asmaster regulator TFs. E2F7 was described as a transcriptionalrepressor of cell cycle-related protein-coding genes andproliferation-promoting miRNAs. On the other hand, TCF4 is associatedwith the Wnt/beta-catenin pathway, playing a critical role in cellproliferation and survival when overexpressed,whileits downregulation can contribute to apoptosis. CONCLUSION:Herein, we identifiednine DEGs with overlapping among two microarrays at 2 Gy of ionizingradiation and 24 h post-exposure of white blood cells irradiated.These DEGs were associated with relevant processes and pathwaysinvolved in DNA damage signaling and repair after ionizing radiationexposure. In addition, we detected among them, two master regulatorTFs. Thus, further studies on these genes will be conducted in orderto validate their potential application as biomarkers of ionizingradiation exposure for biodosimetry studies