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Title: Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells

Abstract

Radiation induced genomic instability is a well-studied phenomenon, the underlying mechanisms of which are poorly understood. Persistent oxidative stress, mitochondrial dysfunction, elevated cytokine levels and epigenetic changes are among the mechanisms invoked in the perpetuation of the phenotype. To determine whether epigenetic aberrations affect genomic instability we measured DNA methylation, mRNA and microRNA (miR) levels in well characterized chromosomally stable and unstable clonally expanded single cell survivors of irradiation. While no changes in DNA methylation were observed for the gene promoters evaluated, increased LINE-1 methylation was observed for two unstable clones (LS12, CS9) and decreased Alu element methylation was observed for the other two unstable clones (115, Fe5.0-8). These relationships also manifested for mRNA and miR expression. mRNA identified for the LS12 and CS9 clones were most similar to each other (261 mRNA), while the 115 and Fe5.0-8 clones were more similar to each other, and surprisingly also similar to the two stable clones, 114 and 118 (286 mRNA among these four clones). Pathway analysis showed enrichment for pathways involved in mitochondrial function and cellular redox, themes routinely invoked in genomic instability. The commonalities between the two subgroups of clones were also observed for miR. The number of miR formore » which anti-correlated mRNA were identified suggests that these miR exert functional effects in each clone. The results of this study demonstrate significant genetic and epigenetic changes in unstable cells, but similar changes almost equally common in chromosomally stable cells. Possible conclusions might be that the chromosomally stable clones have some other form of instability, or that some of the observed changes represent a sort of radiation signature for and that other changes are related to genomic instability. Irrespective, these findings again suggest that a spectrum of changes both drive genomic instability and permit unstable cells to persist and proliferate.« less

Authors:
; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1167603
Report Number(s):
PNNL-SA-103002
KP1602020
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
PLoS One, 9(9):e107722
Additional Journal Information:
Journal Name: PLoS One, 9(9):e107722
Country of Publication:
United States
Language:
English

Citation Formats

Baulch, Janet E., Aypar, Umut, Waters, Katrina M., Yang, Austin, and Morgan, William F. Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells. United States: N. p., 2014. Web. doi:10.1371/journal.pone.0107722.
Baulch, Janet E., Aypar, Umut, Waters, Katrina M., Yang, Austin, & Morgan, William F. Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells. United States. doi:10.1371/journal.pone.0107722.
Baulch, Janet E., Aypar, Umut, Waters, Katrina M., Yang, Austin, and Morgan, William F. Wed . "Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells". United States. doi:10.1371/journal.pone.0107722.
@article{osti_1167603,
title = {Genetic and Epigenetic Changes in Chromosomally Stable and Unstable Progeny of Irradiated Cells},
author = {Baulch, Janet E. and Aypar, Umut and Waters, Katrina M. and Yang, Austin and Morgan, William F.},
abstractNote = {Radiation induced genomic instability is a well-studied phenomenon, the underlying mechanisms of which are poorly understood. Persistent oxidative stress, mitochondrial dysfunction, elevated cytokine levels and epigenetic changes are among the mechanisms invoked in the perpetuation of the phenotype. To determine whether epigenetic aberrations affect genomic instability we measured DNA methylation, mRNA and microRNA (miR) levels in well characterized chromosomally stable and unstable clonally expanded single cell survivors of irradiation. While no changes in DNA methylation were observed for the gene promoters evaluated, increased LINE-1 methylation was observed for two unstable clones (LS12, CS9) and decreased Alu element methylation was observed for the other two unstable clones (115, Fe5.0-8). These relationships also manifested for mRNA and miR expression. mRNA identified for the LS12 and CS9 clones were most similar to each other (261 mRNA), while the 115 and Fe5.0-8 clones were more similar to each other, and surprisingly also similar to the two stable clones, 114 and 118 (286 mRNA among these four clones). Pathway analysis showed enrichment for pathways involved in mitochondrial function and cellular redox, themes routinely invoked in genomic instability. The commonalities between the two subgroups of clones were also observed for miR. The number of miR for which anti-correlated mRNA were identified suggests that these miR exert functional effects in each clone. The results of this study demonstrate significant genetic and epigenetic changes in unstable cells, but similar changes almost equally common in chromosomally stable cells. Possible conclusions might be that the chromosomally stable clones have some other form of instability, or that some of the observed changes represent a sort of radiation signature for and that other changes are related to genomic instability. Irrespective, these findings again suggest that a spectrum of changes both drive genomic instability and permit unstable cells to persist and proliferate.},
doi = {10.1371/journal.pone.0107722},
journal = {PLoS One, 9(9):e107722},
number = ,
volume = ,
place = {United States},
year = {2014},
month = {9}
}