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Analysis of the heat shock response in mouse liver reveals transcriptional dependence on the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha).

Vallanat B, Anderson SP, Brown-Borg HM, Ren H, Kersten S, Jonnalagadda S, Srinivasan R, Corton JC - BMC Genomics (2010)

Bottom Line: However, most of the targets of HS did not overlap between strains.A subset of genes was shown by microarray and RT-PCR to be regulated by HS in a PPARalpha-dependent manner.These findings demonstrate that the PPARalpha genotype has a dramatic effect on the transcriptional targets of HS and support an expanded role for PPARalpha in the regulation of proteome maintenance genes after exposure to diverse forms of environmental stress including HS.

View Article: PubMed Central - HTML - PubMed

Affiliation: NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC 27711, USA. corton.chris@epa.gov

ABSTRACT

Background: The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) regulates responses to chemical or physical stress in part by altering expression of genes involved in proteome maintenance. Many of these genes are also transcriptionally regulated by heat shock (HS) through activation by HS factor-1 (HSF1). We hypothesized that there are interactions on a genetic level between PPARalpha and the HS response mediated by HSF1.

Results: Wild-type and PPARalpha- mice were exposed to HS, the PPARalpha agonist WY-14,643 (WY), or both; gene and protein expression was examined in the livers of the mice 4 or 24 hrs after HS. Gene expression profiling identified a number of Hsp family members that were altered similarly in both mouse strains. However, most of the targets of HS did not overlap between strains. A subset of genes was shown by microarray and RT-PCR to be regulated by HS in a PPARalpha-dependent manner. HS also down-regulated a large set of mitochondrial genes specifically in PPARalpha- mice that are known targets of PPARgamma co-activator-1 (PGC-1) family members. Pretreatment of PPARalpha- mice with WY increased expression of PGC-1beta and target genes and prevented the down-regulation of the mitochondrial genes by HS. A comparison of HS genes regulated in our dataset with those identified in wild-type and HSF1- mouse embryonic fibroblasts indicated that although many HS genes are regulated independently of both PPARalpha and HSF1, a number require both factors for HS responsiveness.

Conclusions: These findings demonstrate that the PPARalpha genotype has a dramatic effect on the transcriptional targets of HS and support an expanded role for PPARalpha in the regulation of proteome maintenance genes after exposure to diverse forms of environmental stress including HS.

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Global decreases in mitochondrial gene expression in PPARα- mice after heat shock are prevented by WY pretreatment. A. Down-regulation of genes regulated by the co-activator PGC-1. Gene Set Enrichment Analysis (GSEA) was used to identify gene sets that exhibited significant overlaps with those gene differences between control and HS in PPARα- mice. Left, enrichment plot for genes regulated by PGC-1. Black bars illustrate the position of probe sets belonging to the PGC-1 gene set in the context of all probes on the U74Av2 array. The running enrichment score (RES) plotted as a function of the position within the ranked list of array probes is shown as a green line. The ranked list metric shown in gray illustrates the correlation between the signal to noise values of all individually ranked genes according to the class labels (experimental conditions). Right, individual expression profiles for leading edge probe sets contributing to the normalized enrichment score are shown. Signal intensities are illustrated by varying shades of red (up-regulation) and blue (down-regulation). B. Prevention of down-regulation of electron transporter gene expression by pretreatment with WY. Left, enrichment plot for genes with electron transporter activity as described in A. Right, individual expression profiles for probe sets contributing to the normalized enrichment score are shown. C. Increased expression of PGC1β and regulated genes involved in lipid homeostasis by WY in PPARα- mice. GSEA-derived heat map of the top 100 differentially expressed probe sets enriched in the control or WY-treated groups from PPARα- mice. Location of PGC1β (Ppargc1b) and regulated genes are indicated. D. Increased expression of genes involved in fatty acid metabolism after exposure to WY for 5 days in PPARα- mice. Genes significantly altered in the GSEA set "fatty acid metabolism" are shown. These include a number that overlap with those that are involved in mitochondrial fatty acid metabolism regulated by PGC-1.
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Figure 6: Global decreases in mitochondrial gene expression in PPARα- mice after heat shock are prevented by WY pretreatment. A. Down-regulation of genes regulated by the co-activator PGC-1. Gene Set Enrichment Analysis (GSEA) was used to identify gene sets that exhibited significant overlaps with those gene differences between control and HS in PPARα- mice. Left, enrichment plot for genes regulated by PGC-1. Black bars illustrate the position of probe sets belonging to the PGC-1 gene set in the context of all probes on the U74Av2 array. The running enrichment score (RES) plotted as a function of the position within the ranked list of array probes is shown as a green line. The ranked list metric shown in gray illustrates the correlation between the signal to noise values of all individually ranked genes according to the class labels (experimental conditions). Right, individual expression profiles for leading edge probe sets contributing to the normalized enrichment score are shown. Signal intensities are illustrated by varying shades of red (up-regulation) and blue (down-regulation). B. Prevention of down-regulation of electron transporter gene expression by pretreatment with WY. Left, enrichment plot for genes with electron transporter activity as described in A. Right, individual expression profiles for probe sets contributing to the normalized enrichment score are shown. C. Increased expression of PGC1β and regulated genes involved in lipid homeostasis by WY in PPARα- mice. GSEA-derived heat map of the top 100 differentially expressed probe sets enriched in the control or WY-treated groups from PPARα- mice. Location of PGC1β (Ppargc1b) and regulated genes are indicated. D. Increased expression of genes involved in fatty acid metabolism after exposure to WY for 5 days in PPARα- mice. Genes significantly altered in the GSEA set "fatty acid metabolism" are shown. These include a number that overlap with those that are involved in mitochondrial fatty acid metabolism regulated by PGC-1.

Mentions: HS can induce mitochondrial swelling, loss of mitochondria and uncoupling of oxidative phosphorylation [45]. HS in PPARα- mice led to dramatic decreases in mitochondrial biogenesis and mitochondrial oxidative phosphorylation genes regulated by PGC-1 family members (Additional File 6). Coordinated down-regulation of a curated set of genes regulated by PGC-1 was observed; out of the 310 genes in this list shared by the U74Av2 array, 123 were down-regulated (Figure 6A). Pretreatment of PPARα- mice with WY led to resistance to gene expression changes, as far fewer genes were altered by both treatments compared to HS alone (774 genes for HS alone vs. 68 genes for HS+WY). We compared the two groups directly using GSEA and identified significant increases in electron transporter genes after HS+WY treatment compared to HS alone including those that function in the mitochondria (Figure 6B). Significant alterations in mitochondrial gene sets were not observed in a comparison between control and HS+WY groups using GSEA (data not shown). Thus, WY pretreatment of PPARα- mice prevented decreases in mitochondrial gene expression due to HS.


Analysis of the heat shock response in mouse liver reveals transcriptional dependence on the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha).

Vallanat B, Anderson SP, Brown-Borg HM, Ren H, Kersten S, Jonnalagadda S, Srinivasan R, Corton JC - BMC Genomics (2010)

Global decreases in mitochondrial gene expression in PPARα- mice after heat shock are prevented by WY pretreatment. A. Down-regulation of genes regulated by the co-activator PGC-1. Gene Set Enrichment Analysis (GSEA) was used to identify gene sets that exhibited significant overlaps with those gene differences between control and HS in PPARα- mice. Left, enrichment plot for genes regulated by PGC-1. Black bars illustrate the position of probe sets belonging to the PGC-1 gene set in the context of all probes on the U74Av2 array. The running enrichment score (RES) plotted as a function of the position within the ranked list of array probes is shown as a green line. The ranked list metric shown in gray illustrates the correlation between the signal to noise values of all individually ranked genes according to the class labels (experimental conditions). Right, individual expression profiles for leading edge probe sets contributing to the normalized enrichment score are shown. Signal intensities are illustrated by varying shades of red (up-regulation) and blue (down-regulation). B. Prevention of down-regulation of electron transporter gene expression by pretreatment with WY. Left, enrichment plot for genes with electron transporter activity as described in A. Right, individual expression profiles for probe sets contributing to the normalized enrichment score are shown. C. Increased expression of PGC1β and regulated genes involved in lipid homeostasis by WY in PPARα- mice. GSEA-derived heat map of the top 100 differentially expressed probe sets enriched in the control or WY-treated groups from PPARα- mice. Location of PGC1β (Ppargc1b) and regulated genes are indicated. D. Increased expression of genes involved in fatty acid metabolism after exposure to WY for 5 days in PPARα- mice. Genes significantly altered in the GSEA set "fatty acid metabolism" are shown. These include a number that overlap with those that are involved in mitochondrial fatty acid metabolism regulated by PGC-1.
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Figure 6: Global decreases in mitochondrial gene expression in PPARα- mice after heat shock are prevented by WY pretreatment. A. Down-regulation of genes regulated by the co-activator PGC-1. Gene Set Enrichment Analysis (GSEA) was used to identify gene sets that exhibited significant overlaps with those gene differences between control and HS in PPARα- mice. Left, enrichment plot for genes regulated by PGC-1. Black bars illustrate the position of probe sets belonging to the PGC-1 gene set in the context of all probes on the U74Av2 array. The running enrichment score (RES) plotted as a function of the position within the ranked list of array probes is shown as a green line. The ranked list metric shown in gray illustrates the correlation between the signal to noise values of all individually ranked genes according to the class labels (experimental conditions). Right, individual expression profiles for leading edge probe sets contributing to the normalized enrichment score are shown. Signal intensities are illustrated by varying shades of red (up-regulation) and blue (down-regulation). B. Prevention of down-regulation of electron transporter gene expression by pretreatment with WY. Left, enrichment plot for genes with electron transporter activity as described in A. Right, individual expression profiles for probe sets contributing to the normalized enrichment score are shown. C. Increased expression of PGC1β and regulated genes involved in lipid homeostasis by WY in PPARα- mice. GSEA-derived heat map of the top 100 differentially expressed probe sets enriched in the control or WY-treated groups from PPARα- mice. Location of PGC1β (Ppargc1b) and regulated genes are indicated. D. Increased expression of genes involved in fatty acid metabolism after exposure to WY for 5 days in PPARα- mice. Genes significantly altered in the GSEA set "fatty acid metabolism" are shown. These include a number that overlap with those that are involved in mitochondrial fatty acid metabolism regulated by PGC-1.
Mentions: HS can induce mitochondrial swelling, loss of mitochondria and uncoupling of oxidative phosphorylation [45]. HS in PPARα- mice led to dramatic decreases in mitochondrial biogenesis and mitochondrial oxidative phosphorylation genes regulated by PGC-1 family members (Additional File 6). Coordinated down-regulation of a curated set of genes regulated by PGC-1 was observed; out of the 310 genes in this list shared by the U74Av2 array, 123 were down-regulated (Figure 6A). Pretreatment of PPARα- mice with WY led to resistance to gene expression changes, as far fewer genes were altered by both treatments compared to HS alone (774 genes for HS alone vs. 68 genes for HS+WY). We compared the two groups directly using GSEA and identified significant increases in electron transporter genes after HS+WY treatment compared to HS alone including those that function in the mitochondria (Figure 6B). Significant alterations in mitochondrial gene sets were not observed in a comparison between control and HS+WY groups using GSEA (data not shown). Thus, WY pretreatment of PPARα- mice prevented decreases in mitochondrial gene expression due to HS.

Bottom Line: However, most of the targets of HS did not overlap between strains.A subset of genes was shown by microarray and RT-PCR to be regulated by HS in a PPARalpha-dependent manner.These findings demonstrate that the PPARalpha genotype has a dramatic effect on the transcriptional targets of HS and support an expanded role for PPARalpha in the regulation of proteome maintenance genes after exposure to diverse forms of environmental stress including HS.

View Article: PubMed Central - HTML - PubMed

Affiliation: NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC 27711, USA. corton.chris@epa.gov

ABSTRACT

Background: The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) regulates responses to chemical or physical stress in part by altering expression of genes involved in proteome maintenance. Many of these genes are also transcriptionally regulated by heat shock (HS) through activation by HS factor-1 (HSF1). We hypothesized that there are interactions on a genetic level between PPARalpha and the HS response mediated by HSF1.

Results: Wild-type and PPARalpha- mice were exposed to HS, the PPARalpha agonist WY-14,643 (WY), or both; gene and protein expression was examined in the livers of the mice 4 or 24 hrs after HS. Gene expression profiling identified a number of Hsp family members that were altered similarly in both mouse strains. However, most of the targets of HS did not overlap between strains. A subset of genes was shown by microarray and RT-PCR to be regulated by HS in a PPARalpha-dependent manner. HS also down-regulated a large set of mitochondrial genes specifically in PPARalpha- mice that are known targets of PPARgamma co-activator-1 (PGC-1) family members. Pretreatment of PPARalpha- mice with WY increased expression of PGC-1beta and target genes and prevented the down-regulation of the mitochondrial genes by HS. A comparison of HS genes regulated in our dataset with those identified in wild-type and HSF1- mouse embryonic fibroblasts indicated that although many HS genes are regulated independently of both PPARalpha and HSF1, a number require both factors for HS responsiveness.

Conclusions: These findings demonstrate that the PPARalpha genotype has a dramatic effect on the transcriptional targets of HS and support an expanded role for PPARalpha in the regulation of proteome maintenance genes after exposure to diverse forms of environmental stress including HS.

Show MeSH
Related in: MedlinePlus