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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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Related in: MedlinePlus

Regulation of heat shock genes by HSF1 and PPARα. Genes which exhibited significant changes in expression due to HS from the dataset of Trinklein et al. (2004) and from the present study were identified. A. Heat map of gene expression changes by HS in wild-type (W) and PPARα- (N) mice compared to the Trinklein et al. (2004) dataset. In the Trinklein et al. (2004) study, mouse embryonic fibroblasts were subjected to HS followed by recovery for the indicated times in hrs. Genes were subjected to one-dimensional hierarchical clustering. Red, up-regulation; green, down-regulation; grey, no data; black, no change. B. Classification of genes based on regulation by PPARα and HSF1.
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Figure 7: Regulation of heat shock genes by HSF1 and PPARα. Genes which exhibited significant changes in expression due to HS from the dataset of Trinklein et al. (2004) and from the present study were identified. A. Heat map of gene expression changes by HS in wild-type (W) and PPARα- (N) mice compared to the Trinklein et al. (2004) dataset. In the Trinklein et al. (2004) study, mouse embryonic fibroblasts were subjected to HS followed by recovery for the indicated times in hrs. Genes were subjected to one-dimensional hierarchical clustering. Red, up-regulation; green, down-regulation; grey, no data; black, no change. B. Classification of genes based on regulation by PPARα and HSF1.

Mentions: HSF1 controls expression of Hsp genes after HS [7,8]. We determined if there was any overlap in HS genes regulated by HSF1 and PPARα. We identified a number of classes of HSF1-dependent or -independent genes regulated by HS as well as genes that require HSF1 for basal expression (Additional File 10 and 11). We then identified genes that overlapped with those regulated by HS in wild-type and PPARα- mice from our study. The expression of the 45 unique pairs of gene identifiers from each array is shown in Figure 7A.


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)

Regulation of heat shock genes by HSF1 and PPARα. Genes which exhibited significant changes in expression due to HS from the dataset of Trinklein et al. (2004) and from the present study were identified. A. Heat map of gene expression changes by HS in wild-type (W) and PPARα- (N) mice compared to the Trinklein et al. (2004) dataset. In the Trinklein et al. (2004) study, mouse embryonic fibroblasts were subjected to HS followed by recovery for the indicated times in hrs. Genes were subjected to one-dimensional hierarchical clustering. Red, up-regulation; green, down-regulation; grey, no data; black, no change. B. Classification of genes based on regulation by PPARα and HSF1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2823686&req=5

Figure 7: Regulation of heat shock genes by HSF1 and PPARα. Genes which exhibited significant changes in expression due to HS from the dataset of Trinklein et al. (2004) and from the present study were identified. A. Heat map of gene expression changes by HS in wild-type (W) and PPARα- (N) mice compared to the Trinklein et al. (2004) dataset. In the Trinklein et al. (2004) study, mouse embryonic fibroblasts were subjected to HS followed by recovery for the indicated times in hrs. Genes were subjected to one-dimensional hierarchical clustering. Red, up-regulation; green, down-regulation; grey, no data; black, no change. B. Classification of genes based on regulation by PPARα and HSF1.
Mentions: HSF1 controls expression of Hsp genes after HS [7,8]. We determined if there was any overlap in HS genes regulated by HSF1 and PPARα. We identified a number of classes of HSF1-dependent or -independent genes regulated by HS as well as genes that require HSF1 for basal expression (Additional File 10 and 11). We then identified genes that overlapped with those regulated by HS in wild-type and PPARα- mice from our study. The expression of the 45 unique pairs of gene identifiers from each array is shown in Figure 7A.

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