Data integration reveals key homeostatic mechanisms following low dose radiation exposure

• Published in: Toxicology and applied pharmacology Vol. 285; no. 1; pp. 1 - 11
• Main Authors: Tilton, Susan C., Matzke, Melissa M., Sowa, Marianne B., Stenoien, David L., Weber, Thomas J., Morgan, William F., Waters, Katrina M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.05.2015
• Subjects: Cells, Cultured; Coculture Techniques; Fibroblasts - metabolism; Fibroblasts - pathology; Fibroblasts - radiation effects; Gene Expression Regulation - radiation effects; Gene Regulatory Networks - radiation effects; Genomics; High-Throughput Screening Assays; Homeostasis; Humans; Infant, Newborn; Ionizing radiation; Keratinocytes - metabolism; Keratinocytes - pathology; Keratinocytes - radiation effects; Male; Metabolomics; Oxidative stress; Oxidative Stress - radiation effects; Phosphoproteins - metabolism; Protein Interaction Maps - radiation effects; Proteomics; Radiation Dosage; Signal Transduction - radiation effects; Skin; Skin - metabolism; Skin - pathology; Skin - radiation effects; Systems Biology - methods; Time Factors; RNA; Genomics; TOPBP; H2O2; YY1; Ionizing radiation; CCND1; CASP3; MYC; TIMP1; PBS; ARG1; TOP1/2; ER; K14; CREB1; NOS; DDAH1; ROS; MCM3; Skin; PIP2; CDK1/2; NO; Oxidative stress; Metabolomics; FT; yH2AX; ANOVA; FDR; GC–MS; MMP1/2; PLK1; CDC7; BAK; MKi67; SOD2; ECM; CDC2; ECL; Der; SP1; EdU; Proteomics; iTRAQ; BAX; ATR; Epi; SPANS
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.01.019

The goal of this study was to define pathways regulated by low dose radiation to understand how biological systems respond to subtle perturbations in their environment and prioritize pathways for human health assessment. Using an in vitro 3-D human full thickness skin model, we have examined the temporal response of dermal and epidermal layers to 10cGy X-ray using transcriptomic, proteomic, phosphoproteomic and metabolomic platforms. Bioinformatics analysis of each dataset independently revealed potential signaling mechanisms affected by low dose radiation, and integrating data shed additional insight into the mechanisms regulating low dose responses in human tissue. We examined direct interactions among datasets (top down approach) and defined several hubs as significant regulators, including transcription factors (YY1, MYC and CREB1), kinases (CDK2, PLK1) and a protease (MMP2). These data indicate a shift in response across time — with an increase in DNA repair, tissue remodeling and repression of cell proliferation acutely (24–72h). Pathway-based integration (bottom up approach) identified common molecular and pathway responses to low dose radiation, including oxidative stress, nitric oxide signaling and transcriptional regulation through the SP1 factor that would not have been identified by the individual data sets. Significant regulation of key downstream metabolites of nitrative stress was measured within these pathways. Among the features identified in our study, the regulation of MMP2 and SP1 was experimentally validated. Our results demonstrate the advantage of data integration to broadly define the pathways and networks that represent the mechanisms by which complex biological systems respond to perturbation. •Low dose ionizing radiation altered homeostasis in 3D skin tissue model.•Global gene/protein/metabolite data integrated using complementary statistical approaches•Time and location-specific change in matrix regulation, ROS/RNS and DNA repair pathways detected•Low dose exposure alters metabolites involved in nitric oxide biosynthesis and wound healing.•Computationally predicted regulators of primary mechanisms were experimentally validated.