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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

Chromosomal location of clustered radiation responsive genes.All genes represented on the exon array that are found on chromosome 6 are shown (A). Four hours after 10 Gy IR, down-regulated genes in LCLs were selected based first on p-value of <0.1 and then the top 500 genes based on fold change were selected and plotted (B). Only the HIST genes (n = 21) on chromosome 6 that are down-regulated in LCLs are plotted (C). Likewise, all genes represented on the exon array that are found on chromosome 11 are shown (D). Four hours after 10 Gy IR, up-regulated genes were selected based first on p-value of <0.1 and then the top 500 genes based on fold change were selected and plotted (E). Only the olfactory receptor genes (OR; n = 17) on chromosome 11 that are up-regulation in LCLs are plotted (F). Blue and red filled circles represent individual genes which made the selection. Colour is based on p-value, blue indicating a lower p-value than red. Chromosome cytobands are represented below the plots with the p-arm of the chromosome towards the right and the q-arm towards the left of the diagram.
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pone-0025758-g011: Chromosomal location of clustered radiation responsive genes.All genes represented on the exon array that are found on chromosome 6 are shown (A). Four hours after 10 Gy IR, down-regulated genes in LCLs were selected based first on p-value of <0.1 and then the top 500 genes based on fold change were selected and plotted (B). Only the HIST genes (n = 21) on chromosome 6 that are down-regulated in LCLs are plotted (C). Likewise, all genes represented on the exon array that are found on chromosome 11 are shown (D). Four hours after 10 Gy IR, up-regulated genes were selected based first on p-value of <0.1 and then the top 500 genes based on fold change were selected and plotted (E). Only the olfactory receptor genes (OR; n = 17) on chromosome 11 that are up-regulation in LCLs are plotted (F). Blue and red filled circles represent individual genes which made the selection. Colour is based on p-value, blue indicating a lower p-value than red. Chromosome cytobands are represented below the plots with the p-arm of the chromosome towards the right and the q-arm towards the left 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)

Chromosomal location of clustered radiation responsive genes.All genes represented on the exon array that are found on chromosome 6 are shown (A). Four hours after 10 Gy IR, down-regulated genes in LCLs were selected based first on p-value of <0.1 and then the top 500 genes based on fold change were selected and plotted (B). Only the HIST genes (n = 21) on chromosome 6 that are down-regulated in LCLs are plotted (C). Likewise, all genes represented on the exon array that are found on chromosome 11 are shown (D). Four hours after 10 Gy IR, up-regulated genes were selected based first on p-value of <0.1 and then the top 500 genes based on fold change were selected and plotted (E). Only the olfactory receptor genes (OR; n = 17) on chromosome 11 that are up-regulation in LCLs are plotted (F). Blue and red filled circles represent individual genes which made the selection. Colour is based on p-value, blue indicating a lower p-value than red. Chromosome cytobands are represented below the plots with the p-arm of the chromosome towards the right and the q-arm towards the left of the diagram.
© Copyright Policy
Related In: Results  -  Collection

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pone-0025758-g011: Chromosomal location of clustered radiation responsive genes.All genes represented on the exon array that are found on chromosome 6 are shown (A). Four hours after 10 Gy IR, down-regulated genes in LCLs were selected based first on p-value of <0.1 and then the top 500 genes based on fold change were selected and plotted (B). Only the HIST genes (n = 21) on chromosome 6 that are down-regulated in LCLs are plotted (C). Likewise, all genes represented on the exon array that are found on chromosome 11 are shown (D). Four hours after 10 Gy IR, up-regulated genes were selected based first on p-value of <0.1 and then the top 500 genes based on fold change were selected and plotted (E). Only the olfactory receptor genes (OR; n = 17) on chromosome 11 that are up-regulation in LCLs are plotted (F). Blue and red filled circles represent individual genes which made the selection. Colour is based on p-value, blue indicating a lower p-value than red. Chromosome cytobands are represented below the plots with the p-arm of the chromosome towards the right and the q-arm towards the left 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