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Transcriptional regulation by poly(ADP-ribose) polymerase-1 during T cell activation.

Saenz L, Lozano JJ, Valdor R, Baroja-Mazo A, Ramirez P, Parrilla P, Aparicio P, Sumoy L, Yélamos J - BMC Genomics (2008)

Bottom Line: Interestingly, PARP-1 deficiency significantly alters expression of genes associated with the immune response such as chemokines and genes involved in the Th1/Th2 balance.This study provides new insights into changes in gene expression mediated by PARP-1 upon T cell activation.Pathway analysis of PARP-1 as a nuclear signalling molecule in T cells would be of relevance for the future development of new therapeutic approaches targeting PARP-1 in the acquired immune response.

View Article: PubMed Central - HTML - PubMed

Affiliation: Transplant Unit, Department of Surgery, University Hospital Virgen de Arrixaca, University of Murcia, Ciberehd, Murcia, Spain. txito3@hotmail.com

ABSTRACT

Background: Accumulating evidence suggests an important role for the enzyme poly(ADP-ribose) polymerase-1 (PARP-1) as an integral part of the gene expression regulatory machinery during development and in response to specific cellular signals. PARP-1 might modulate gene expression through its catalytic activity leading to poly(ADP-ribosyl)ation of nuclear proteins or by its physical association with relevant proteins. Recently, we have shown that PARP-1 is activated during T cell activation. However, the proposed role of PARP-1 in reprogramming T cell gene expression upon activation remains largely unexplored.

Results: In the present study we use oligonucleotide microarray analysis to gain more insight into the role played by PARP-1 during the gene expression reprogramming that takes place in T cells upon activation with anti-CD3 stimulation alone, or in combination with anti-CD28 co-stimulation. We have identified several groups of genes with expression modulated by PARP-1. The expression of 129 early-response genes to anti-CD3 seems to be regulated by PARP-1 either in a positive (45 genes) or in a negative manner (84 genes). Likewise, in the presence of co-stimulation (anti-CD3 + anti-CD28 stimulation), the expression of 203 genes is also regulated by PARP-1 either up (173 genes) or down (30 genes). Interestingly, PARP-1 deficiency significantly alters expression of genes associated with the immune response such as chemokines and genes involved in the Th1/Th2 balance.

Conclusion: This study provides new insights into changes in gene expression mediated by PARP-1 upon T cell activation. Pathway analysis of PARP-1 as a nuclear signalling molecule in T cells would be of relevance for the future development of new therapeutic approaches targeting PARP-1 in the acquired immune response.

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PARP-1 dependent genes in T cells involved in the immune response. (A) Expression maps including all the genes belonging to GO terms "immune response". Red indicates higher expression in Parp-1+/+ T cells compared to Parp-1-/- T cells (positive regulation by PARP-1) while green indicates higher expression in Parp-1-/- T cells compared to Parp-1+/+ T cells (negative regulation by PARP-1). Numbers in the left column indicate the fold-change expression in Parp-1+/+ T cells compared to Parp-1-/- T cells. (B) Real-time PCR analysis of representative genes in response to anti-CD3 stimulation or (C) in response to anti-CD3 + anti-CD28 stimulation. Samples were normalized according to Gapdh expression levels. The y-axis represents fold-change of activated versus resting cells for both Parp-1+/+ (white bars) and Parp-1-/- (black bars) T cells. Results represent the mean value ± SD of two independent experiments. The ratio of gene expression in Parp-1+/+ over Parp-1-/- cells (positive number) or the ratio of gene expression in Parp-1-/- over Parp-1+/+ (negative number) cells is indicated above each pair of bars.
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Figure 3: PARP-1 dependent genes in T cells involved in the immune response. (A) Expression maps including all the genes belonging to GO terms "immune response". Red indicates higher expression in Parp-1+/+ T cells compared to Parp-1-/- T cells (positive regulation by PARP-1) while green indicates higher expression in Parp-1-/- T cells compared to Parp-1+/+ T cells (negative regulation by PARP-1). Numbers in the left column indicate the fold-change expression in Parp-1+/+ T cells compared to Parp-1-/- T cells. (B) Real-time PCR analysis of representative genes in response to anti-CD3 stimulation or (C) in response to anti-CD3 + anti-CD28 stimulation. Samples were normalized according to Gapdh expression levels. The y-axis represents fold-change of activated versus resting cells for both Parp-1+/+ (white bars) and Parp-1-/- (black bars) T cells. Results represent the mean value ± SD of two independent experiments. The ratio of gene expression in Parp-1+/+ over Parp-1-/- cells (positive number) or the ratio of gene expression in Parp-1-/- over Parp-1+/+ (negative number) cells is indicated above each pair of bars.

Mentions: A subset of PARP-1 dependent genes in response to anti-CD3 stimulation (14 out of 129; ~11%) and in response to anti-CD3 + anti-CD28 stimulation (24 out of 203; ~12%) encode for molecules involved directly in the immune response pathway (Fig. 3A) as determined using the Ingenuity software. To validate the array data, we also evaluated expression of several of these genes by quantitative Real-time PCR. Although there were differences in the absolute fold-change values detected by the two methods, PCR results correlated well with the differential gene expression data produced using Affymetrix GeneChips (Fig. 3B and 3C). Discordant results were found between the arrays and PCR for only Gbp7 gene in response to anti-CD3 + anti-CD28 stimulation.


Transcriptional regulation by poly(ADP-ribose) polymerase-1 during T cell activation.

Saenz L, Lozano JJ, Valdor R, Baroja-Mazo A, Ramirez P, Parrilla P, Aparicio P, Sumoy L, Yélamos J - BMC Genomics (2008)

PARP-1 dependent genes in T cells involved in the immune response. (A) Expression maps including all the genes belonging to GO terms "immune response". Red indicates higher expression in Parp-1+/+ T cells compared to Parp-1-/- T cells (positive regulation by PARP-1) while green indicates higher expression in Parp-1-/- T cells compared to Parp-1+/+ T cells (negative regulation by PARP-1). Numbers in the left column indicate the fold-change expression in Parp-1+/+ T cells compared to Parp-1-/- T cells. (B) Real-time PCR analysis of representative genes in response to anti-CD3 stimulation or (C) in response to anti-CD3 + anti-CD28 stimulation. Samples were normalized according to Gapdh expression levels. The y-axis represents fold-change of activated versus resting cells for both Parp-1+/+ (white bars) and Parp-1-/- (black bars) T cells. Results represent the mean value ± SD of two independent experiments. The ratio of gene expression in Parp-1+/+ over Parp-1-/- cells (positive number) or the ratio of gene expression in Parp-1-/- over Parp-1+/+ (negative number) cells is indicated above each pair of bars.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2375913&req=5

Figure 3: PARP-1 dependent genes in T cells involved in the immune response. (A) Expression maps including all the genes belonging to GO terms "immune response". Red indicates higher expression in Parp-1+/+ T cells compared to Parp-1-/- T cells (positive regulation by PARP-1) while green indicates higher expression in Parp-1-/- T cells compared to Parp-1+/+ T cells (negative regulation by PARP-1). Numbers in the left column indicate the fold-change expression in Parp-1+/+ T cells compared to Parp-1-/- T cells. (B) Real-time PCR analysis of representative genes in response to anti-CD3 stimulation or (C) in response to anti-CD3 + anti-CD28 stimulation. Samples were normalized according to Gapdh expression levels. The y-axis represents fold-change of activated versus resting cells for both Parp-1+/+ (white bars) and Parp-1-/- (black bars) T cells. Results represent the mean value ± SD of two independent experiments. The ratio of gene expression in Parp-1+/+ over Parp-1-/- cells (positive number) or the ratio of gene expression in Parp-1-/- over Parp-1+/+ (negative number) cells is indicated above each pair of bars.
Mentions: A subset of PARP-1 dependent genes in response to anti-CD3 stimulation (14 out of 129; ~11%) and in response to anti-CD3 + anti-CD28 stimulation (24 out of 203; ~12%) encode for molecules involved directly in the immune response pathway (Fig. 3A) as determined using the Ingenuity software. To validate the array data, we also evaluated expression of several of these genes by quantitative Real-time PCR. Although there were differences in the absolute fold-change values detected by the two methods, PCR results correlated well with the differential gene expression data produced using Affymetrix GeneChips (Fig. 3B and 3C). Discordant results were found between the arrays and PCR for only Gbp7 gene in response to anti-CD3 + anti-CD28 stimulation.

Bottom Line: Interestingly, PARP-1 deficiency significantly alters expression of genes associated with the immune response such as chemokines and genes involved in the Th1/Th2 balance.This study provides new insights into changes in gene expression mediated by PARP-1 upon T cell activation.Pathway analysis of PARP-1 as a nuclear signalling molecule in T cells would be of relevance for the future development of new therapeutic approaches targeting PARP-1 in the acquired immune response.

View Article: PubMed Central - HTML - PubMed

Affiliation: Transplant Unit, Department of Surgery, University Hospital Virgen de Arrixaca, University of Murcia, Ciberehd, Murcia, Spain. txito3@hotmail.com

ABSTRACT

Background: Accumulating evidence suggests an important role for the enzyme poly(ADP-ribose) polymerase-1 (PARP-1) as an integral part of the gene expression regulatory machinery during development and in response to specific cellular signals. PARP-1 might modulate gene expression through its catalytic activity leading to poly(ADP-ribosyl)ation of nuclear proteins or by its physical association with relevant proteins. Recently, we have shown that PARP-1 is activated during T cell activation. However, the proposed role of PARP-1 in reprogramming T cell gene expression upon activation remains largely unexplored.

Results: In the present study we use oligonucleotide microarray analysis to gain more insight into the role played by PARP-1 during the gene expression reprogramming that takes place in T cells upon activation with anti-CD3 stimulation alone, or in combination with anti-CD28 co-stimulation. We have identified several groups of genes with expression modulated by PARP-1. The expression of 129 early-response genes to anti-CD3 seems to be regulated by PARP-1 either in a positive (45 genes) or in a negative manner (84 genes). Likewise, in the presence of co-stimulation (anti-CD3 + anti-CD28 stimulation), the expression of 203 genes is also regulated by PARP-1 either up (173 genes) or down (30 genes). Interestingly, PARP-1 deficiency significantly alters expression of genes associated with the immune response such as chemokines and genes involved in the Th1/Th2 balance.

Conclusion: This study provides new insights into changes in gene expression mediated by PARP-1 upon T cell activation. Pathway analysis of PARP-1 as a nuclear signalling molecule in T cells would be of relevance for the future development of new therapeutic approaches targeting PARP-1 in the acquired immune response.

Show MeSH
Related in: MedlinePlus