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Gene profiling characteristics of radioadaptive response in AG01522 normal human fibroblasts.

Hou J, Wang F, Kong P, Yu PK, Wang H, Han W - PLoS ONE (2015)

Bottom Line: Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear.In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose.We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose.

View Article: PubMed Central - PubMed

Affiliation: Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.

ABSTRACT
Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose.

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Related in: MedlinePlus

Clustering of GSEA results enriched with positive correlation with increased time profile, for various irradiation groups (viz. 5 cGy, 2 Gy, (5 cGy + 2 Gy) and RAR).The GSEA results were sorted by FDR < 25% or nom p value < 1% thresholds, where appropriate. The heatmap illustrated the gene sets for each irradiation group. The red color codes for the presence of the shown gene sets in a particular group, while the blue color codes for absence of the shown gene sets in a particular group.
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pone.0123316.g004: Clustering of GSEA results enriched with positive correlation with increased time profile, for various irradiation groups (viz. 5 cGy, 2 Gy, (5 cGy + 2 Gy) and RAR).The GSEA results were sorted by FDR < 25% or nom p value < 1% thresholds, where appropriate. The heatmap illustrated the gene sets for each irradiation group. The red color codes for the presence of the shown gene sets in a particular group, while the blue color codes for absence of the shown gene sets in a particular group.

Mentions: In general, for the 5 cGy group, the enriched gene sets with negative correlations (Fig 3) involved unfolded protein response, apoptotic execution, spliceosome, DNA and RNA metabolic processes, G protein activation and signaling amplification, kinase activity, DNA repair and replication, and cell cycle arrest. These showed that the cells initiated many biological processes to respond to the stress within a short time after X-ray exposure. Moreover, the 5 cGy low-dose irradiation also induced gene sets or pathways for lysosome organization, hydrolase activity and histone modification, which led to repair of radiation, induced damages and enriched inclination to positive correlation with timeline (Fig 4). The enrichments with negative and positive correlations are presented in S2 Fig.


Gene profiling characteristics of radioadaptive response in AG01522 normal human fibroblasts.

Hou J, Wang F, Kong P, Yu PK, Wang H, Han W - PLoS ONE (2015)

Clustering of GSEA results enriched with positive correlation with increased time profile, for various irradiation groups (viz. 5 cGy, 2 Gy, (5 cGy + 2 Gy) and RAR).The GSEA results were sorted by FDR < 25% or nom p value < 1% thresholds, where appropriate. The heatmap illustrated the gene sets for each irradiation group. The red color codes for the presence of the shown gene sets in a particular group, while the blue color codes for absence of the shown gene sets in a particular group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401551&req=5

pone.0123316.g004: Clustering of GSEA results enriched with positive correlation with increased time profile, for various irradiation groups (viz. 5 cGy, 2 Gy, (5 cGy + 2 Gy) and RAR).The GSEA results were sorted by FDR < 25% or nom p value < 1% thresholds, where appropriate. The heatmap illustrated the gene sets for each irradiation group. The red color codes for the presence of the shown gene sets in a particular group, while the blue color codes for absence of the shown gene sets in a particular group.
Mentions: In general, for the 5 cGy group, the enriched gene sets with negative correlations (Fig 3) involved unfolded protein response, apoptotic execution, spliceosome, DNA and RNA metabolic processes, G protein activation and signaling amplification, kinase activity, DNA repair and replication, and cell cycle arrest. These showed that the cells initiated many biological processes to respond to the stress within a short time after X-ray exposure. Moreover, the 5 cGy low-dose irradiation also induced gene sets or pathways for lysosome organization, hydrolase activity and histone modification, which led to repair of radiation, induced damages and enriched inclination to positive correlation with timeline (Fig 4). The enrichments with negative and positive correlations are presented in S2 Fig.

Bottom Line: Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear.In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose.We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose.

View Article: PubMed Central - PubMed

Affiliation: Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.

ABSTRACT
Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose.

Show MeSH
Related in: MedlinePlus