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Alternative transcript initiation and splicing as a response to DNA damage.

Sprung CN, Li J, Hovan D, McKay MJ, Forrester HB - PLoS ONE (2011)

Bottom Line: Dose-response and time course kinetics have also been characterized.Interestingly, most genes showing alternative transcript induction maintained these isoforms over the dose range and times tested.This study provides novel insights into alternative transcripts as a mechanism for response to DNA damage and cell stress responses in general.

View Article: PubMed Central - PubMed

Affiliation: Centre for Innate Immunity and Infectious Disease, Monash Institute for Medical Research, Monash University, Clayton, Victoria, Australia. carl.sprung@monash.edu

ABSTRACT
Humans are exposed to the DNA damaging agent, ionizing radiation (IR), from background radiation, medical treatments, occupational and accidental exposures. IR causes changes in transcription, but little is known about alternative transcription in response to IR on a genome-wide basis. These investigations examine the response to IR at the exon level in human cells, using exon arrays to comprehensively characterize radiation-induced transcriptional expression products. Previously uncharacterized alternative transcripts that preferentially occur following IR exposure have been discovered. A large number of genes showed alternative transcription initiation as a response to IR. Dose-response and time course kinetics have also been characterized. Interestingly, most genes showing alternative transcript induction maintained these isoforms over the dose range and times tested. Finally, clusters of co-ordinately up- and down-regulated radiation response genes were identified at specific chromosomal loci. These data provide the first genome-wide view of the transcriptional response to ionizing radiation at the exon level. This study provides novel insights into alternative transcripts as a mechanism for response to DNA damage and cell stress responses in general.

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Related in: MedlinePlus

Chromosome location of genes modulated by IR in LCLs.12 LCLs were irradiated with 10 Gy or sham IR and RNA was isolated 4 hours post-IR. Genes with significant (p-value (Dose)<0.05) up-regulated (blue circles) and down-regulated (red circles) 4 hours after 10 Gy IR are plotted above the chromosome location. Chromosome number is indicated on the right of the diagram.
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pone-0025758-g009: Chromosome location of genes modulated by IR in LCLs.12 LCLs were irradiated with 10 Gy or sham IR and RNA was isolated 4 hours post-IR. Genes with significant (p-value (Dose)<0.05) up-regulated (blue circles) and down-regulated (red circles) 4 hours after 10 Gy IR are plotted above the chromosome location. Chromosome number is indicated on the right of the diagram.

Mentions: The location of IR-modulated genes for each chromosome was determined to identify regions that may have IR-specific regulation. In general, responsive genes four hours post-IR were present throughout the chromosomes and more so in gene-rich regions. Some chromosomes had regional clusters of radiation responsive genes. For example, chromosomes 6 and 11 have regions that show enriched gene expression modulation after IR (Figures 9 and 10). Chromosome 6 has a region enriched for IR-modulated genes in LCLs, many of which are down-regulated HIST genes (Figure 11A–C). In this gene rich region there are locations just adjacent to the HIST cluster for which relatively few genes are down-regulated even though there are many more genes present than HIST genes in the HIST cluster. Of the 61 genes down-regulated on chromosome 6 (p-value<0.1 and 500 top based on fold change), we found 21 (38%) HIST genes, all of which were found at the HIST cluster on chromosome 6. We found down-regulation of HIST genes in both LCL and fibroblast cells although to a lesser extent in the fibroblasts. The gene olfactory receptor gene clusters on chromosome 11 showed many of these genes to be up-regulated (17/61 (28%) up-regulated genes (p-value<0.1 and 500 top based on fold change)) (Figure 11D–F). Comparison of the expected frequencies to the actual genes modulated after IR varied between chromosomes and cell lines. For example, a lower than expected number of radiation responsive genes were found in chromosomes 4, 13 and 21 in LCLs and a particularly higher number than expected were observed for chromosome 18 in fibroblasts (Table S18). There was an overall variation between cell types and between individual chromosomes such as chromosomes 13 and 18 (Table S18).


Alternative transcript initiation and splicing as a response to DNA damage.

Sprung CN, Li J, Hovan D, McKay MJ, Forrester HB - PLoS ONE (2011)

Chromosome location of genes modulated by IR in LCLs.12 LCLs were irradiated with 10 Gy or sham IR and RNA was isolated 4 hours post-IR. Genes with significant (p-value (Dose)<0.05) up-regulated (blue circles) and down-regulated (red circles) 4 hours after 10 Gy IR are plotted above the chromosome location. Chromosome number is indicated on the right of the diagram.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198437&req=5

pone-0025758-g009: Chromosome location of genes modulated by IR in LCLs.12 LCLs were irradiated with 10 Gy or sham IR and RNA was isolated 4 hours post-IR. Genes with significant (p-value (Dose)<0.05) up-regulated (blue circles) and down-regulated (red circles) 4 hours after 10 Gy IR are plotted above the chromosome location. Chromosome number is indicated on the right of the diagram.
Mentions: The location of IR-modulated genes for each chromosome was determined to identify regions that may have IR-specific regulation. In general, responsive genes four hours post-IR were present throughout the chromosomes and more so in gene-rich regions. Some chromosomes had regional clusters of radiation responsive genes. For example, chromosomes 6 and 11 have regions that show enriched gene expression modulation after IR (Figures 9 and 10). Chromosome 6 has a region enriched for IR-modulated genes in LCLs, many of which are down-regulated HIST genes (Figure 11A–C). In this gene rich region there are locations just adjacent to the HIST cluster for which relatively few genes are down-regulated even though there are many more genes present than HIST genes in the HIST cluster. Of the 61 genes down-regulated on chromosome 6 (p-value<0.1 and 500 top based on fold change), we found 21 (38%) HIST genes, all of which were found at the HIST cluster on chromosome 6. We found down-regulation of HIST genes in both LCL and fibroblast cells although to a lesser extent in the fibroblasts. The gene olfactory receptor gene clusters on chromosome 11 showed many of these genes to be up-regulated (17/61 (28%) up-regulated genes (p-value<0.1 and 500 top based on fold change)) (Figure 11D–F). Comparison of the expected frequencies to the actual genes modulated after IR varied between chromosomes and cell lines. For example, a lower than expected number of radiation responsive genes were found in chromosomes 4, 13 and 21 in LCLs and a particularly higher number than expected were observed for chromosome 18 in fibroblasts (Table S18). There was an overall variation between cell types and between individual chromosomes such as chromosomes 13 and 18 (Table S18).

Bottom Line: Dose-response and time course kinetics have also been characterized.Interestingly, most genes showing alternative transcript induction maintained these isoforms over the dose range and times tested.This study provides novel insights into alternative transcripts as a mechanism for response to DNA damage and cell stress responses in general.

View Article: PubMed Central - PubMed

Affiliation: Centre for Innate Immunity and Infectious Disease, Monash Institute for Medical Research, Monash University, Clayton, Victoria, Australia. carl.sprung@monash.edu

ABSTRACT
Humans are exposed to the DNA damaging agent, ionizing radiation (IR), from background radiation, medical treatments, occupational and accidental exposures. IR causes changes in transcription, but little is known about alternative transcription in response to IR on a genome-wide basis. These investigations examine the response to IR at the exon level in human cells, using exon arrays to comprehensively characterize radiation-induced transcriptional expression products. Previously uncharacterized alternative transcripts that preferentially occur following IR exposure have been discovered. A large number of genes showed alternative transcription initiation as a response to IR. Dose-response and time course kinetics have also been characterized. Interestingly, most genes showing alternative transcript induction maintained these isoforms over the dose range and times tested. Finally, clusters of co-ordinately up- and down-regulated radiation response genes were identified at specific chromosomal loci. These data provide the first genome-wide view of the transcriptional response to ionizing radiation at the exon level. This study provides novel insights into alternative transcripts as a mechanism for response to DNA damage and cell stress responses in general.

Show MeSH
Related in: MedlinePlus