skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Data Integration Reveals Key Homeostatic Mechanisms Following Low Dose Radiation Exposure

Abstract

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 10 cGy 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 – 72 hr). 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 ofmore » nitrative stress were measured within these pathways. Among the features identified in our study, the regulation of MMP2 and SP1 were 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.« less

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1182927
Report Number(s):
PNNL-SA-102570
KP1602020
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology, 285(2):1-11
Additional Journal Information:
Journal Name: Toxicology and Applied Pharmacology, 285(2):1-11
Country of Publication:
United States
Language:
English
Subject:
radiation; skin; transcriptomics; proteomics; metabolomics

Citation Formats

Tilton, Susan C., Matzke, Melissa M., Sowa, Marianne B., Stenoien, David L., Weber, Thomas J., Morgan, William F., and Waters, Katrina M. Data Integration Reveals Key Homeostatic Mechanisms Following Low Dose Radiation Exposure. United States: N. p., 2015. Web. doi:10.1016/j.taap.2015.01.019.
Tilton, Susan C., Matzke, Melissa M., Sowa, Marianne B., Stenoien, David L., Weber, Thomas J., Morgan, William F., & Waters, Katrina M. Data Integration Reveals Key Homeostatic Mechanisms Following Low Dose Radiation Exposure. United States. doi:10.1016/j.taap.2015.01.019.
Tilton, Susan C., Matzke, Melissa M., Sowa, Marianne B., Stenoien, David L., Weber, Thomas J., Morgan, William F., and Waters, Katrina M. Fri . "Data Integration Reveals Key Homeostatic Mechanisms Following Low Dose Radiation Exposure". United States. doi:10.1016/j.taap.2015.01.019.
@article{osti_1182927,
title = {Data Integration Reveals Key Homeostatic Mechanisms Following Low Dose Radiation Exposure},
author = {Tilton, Susan C. and Matzke, Melissa M. and Sowa, Marianne B. and Stenoien, David L. and Weber, Thomas J. and Morgan, William F. and Waters, Katrina M.},
abstractNote = {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 10 cGy 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 – 72 hr). 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 were measured within these pathways. Among the features identified in our study, the regulation of MMP2 and SP1 were 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.},
doi = {10.1016/j.taap.2015.01.019},
journal = {Toxicology and Applied Pharmacology, 285(2):1-11},
number = ,
volume = ,
place = {United States},
year = {2015},
month = {5}
}