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Transcriptomic analysis unveils correlations between regulative apoptotic caspases and genes of cholesterol homeostasis in human brain.

Picco R, Tomasella A, Fogolari F, Brancolini C - PLoS ONE (2014)

Bottom Line: In the brain, hierarchical clustering has revealed that the expression of regulative apoptotic caspases (CASP2, CASP8 CASP9, CASP10) and of the inflammatory CASP1 is linked to several genes involved in cholesterol homeostasis.We have also demonstrated that these correlations are tissue specific being reduced (CASP9 and CASP10) or different (CASP2) in the liver.For some caspases (CASP1, CASP6 and CASP7) these correlations could be related to brain aging.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical and Biological Sciences, Università degli Studi di Udine, Udine, Italy.

ABSTRACT
Regulative circuits controlling expression of genes involved in the same biological processes are frequently interconnected. These circuits operate to coordinate the expression of multiple genes and also to compensate dysfunctions in specific elements of the network. Caspases are cysteine-proteases with key roles in the execution phase of apoptosis. Silencing of caspase-2 expression in cultured glioblastoma cells allows the up-regulation of a limited number of genes, among which some are related to cholesterol homeostasis. Lysosomal Acid Lipase A (LIPA) was up-regulated in two different cell lines in response to caspase-2 down-regulation and cells silenced for caspase-2 exhibit reduced cholesterol staining in the lipid droplets. We expanded this observation by large-scale analysis of mRNA expression. All caspases were analyzed in terms of co-expression in comparison with 166 genes involved in cholesterol homeostasis. In the brain, hierarchical clustering has revealed that the expression of regulative apoptotic caspases (CASP2, CASP8 CASP9, CASP10) and of the inflammatory CASP1 is linked to several genes involved in cholesterol homeostasis. These correlations resulted in altered GBM (Glioblastoma Multiforme), in particular for CASP1. We have also demonstrated that these correlations are tissue specific being reduced (CASP9 and CASP10) or different (CASP2) in the liver. For some caspases (CASP1, CASP6 and CASP7) these correlations could be related to brain aging.

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Related in: MedlinePlus

Co-expression analysis of caspases and cholesterol genes in human liver.Correlations of expression levels between caspases and cholesterol genes in different liver samples, for the indicated categories. Data obtained were used to calculate the correlation values with the Pearson method. In the heat map positive values are displayed in blue and negative in dark green. The dendrograms displayed on the top are based on hierarchical clustering using the complete linkage method.
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pone-0110610-g007: Co-expression analysis of caspases and cholesterol genes in human liver.Correlations of expression levels between caspases and cholesterol genes in different liver samples, for the indicated categories. Data obtained were used to calculate the correlation values with the Pearson method. In the heat map positive values are displayed in blue and negative in dark green. The dendrograms displayed on the top are based on hierarchical clustering using the complete linkage method.

Mentions: To understand whether our discoveries are limited to CNS or can be observed also in other tissues, we decided to compare variations in the expression levels of caspases and of cholesterol genes in human liver, an essential organ for cholesterol homeostasis. Gene expression profiles from 5 datasets including 106 microarrays of normal human liver were interrogated. Figure 7 shows that correlations among cholesterol genes and expression of regulative apoptotic caspases are less pronounced and only in some categories: transcriptional regulators, cholesterol biosynthesis, steroid and bile acid synthesis, these genes cluster together. In the liver CASP7 reaches the highest scores both for positive and negative correlations. For example CASP7 expression is strongly inversely correlated with those of several apolipoprotein genes, but it positively correlates with NPC1, VLDLR, SOAT1, SNX17 and VPS4B (Table S7); which are genes involved in cholesterol up-take and storage. It is important to note that similarly to caspase-2, caspase-7 expression is under the influence of Srebp1/2 and of statins [87].


Transcriptomic analysis unveils correlations between regulative apoptotic caspases and genes of cholesterol homeostasis in human brain.

Picco R, Tomasella A, Fogolari F, Brancolini C - PLoS ONE (2014)

Co-expression analysis of caspases and cholesterol genes in human liver.Correlations of expression levels between caspases and cholesterol genes in different liver samples, for the indicated categories. Data obtained were used to calculate the correlation values with the Pearson method. In the heat map positive values are displayed in blue and negative in dark green. The dendrograms displayed on the top are based on hierarchical clustering using the complete linkage method.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199739&req=5

pone-0110610-g007: Co-expression analysis of caspases and cholesterol genes in human liver.Correlations of expression levels between caspases and cholesterol genes in different liver samples, for the indicated categories. Data obtained were used to calculate the correlation values with the Pearson method. In the heat map positive values are displayed in blue and negative in dark green. The dendrograms displayed on the top are based on hierarchical clustering using the complete linkage method.
Mentions: To understand whether our discoveries are limited to CNS or can be observed also in other tissues, we decided to compare variations in the expression levels of caspases and of cholesterol genes in human liver, an essential organ for cholesterol homeostasis. Gene expression profiles from 5 datasets including 106 microarrays of normal human liver were interrogated. Figure 7 shows that correlations among cholesterol genes and expression of regulative apoptotic caspases are less pronounced and only in some categories: transcriptional regulators, cholesterol biosynthesis, steroid and bile acid synthesis, these genes cluster together. In the liver CASP7 reaches the highest scores both for positive and negative correlations. For example CASP7 expression is strongly inversely correlated with those of several apolipoprotein genes, but it positively correlates with NPC1, VLDLR, SOAT1, SNX17 and VPS4B (Table S7); which are genes involved in cholesterol up-take and storage. It is important to note that similarly to caspase-2, caspase-7 expression is under the influence of Srebp1/2 and of statins [87].

Bottom Line: In the brain, hierarchical clustering has revealed that the expression of regulative apoptotic caspases (CASP2, CASP8 CASP9, CASP10) and of the inflammatory CASP1 is linked to several genes involved in cholesterol homeostasis.We have also demonstrated that these correlations are tissue specific being reduced (CASP9 and CASP10) or different (CASP2) in the liver.For some caspases (CASP1, CASP6 and CASP7) these correlations could be related to brain aging.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical and Biological Sciences, Università degli Studi di Udine, Udine, Italy.

ABSTRACT
Regulative circuits controlling expression of genes involved in the same biological processes are frequently interconnected. These circuits operate to coordinate the expression of multiple genes and also to compensate dysfunctions in specific elements of the network. Caspases are cysteine-proteases with key roles in the execution phase of apoptosis. Silencing of caspase-2 expression in cultured glioblastoma cells allows the up-regulation of a limited number of genes, among which some are related to cholesterol homeostasis. Lysosomal Acid Lipase A (LIPA) was up-regulated in two different cell lines in response to caspase-2 down-regulation and cells silenced for caspase-2 exhibit reduced cholesterol staining in the lipid droplets. We expanded this observation by large-scale analysis of mRNA expression. All caspases were analyzed in terms of co-expression in comparison with 166 genes involved in cholesterol homeostasis. In the brain, hierarchical clustering has revealed that the expression of regulative apoptotic caspases (CASP2, CASP8 CASP9, CASP10) and of the inflammatory CASP1 is linked to several genes involved in cholesterol homeostasis. These correlations resulted in altered GBM (Glioblastoma Multiforme), in particular for CASP1. We have also demonstrated that these correlations are tissue specific being reduced (CASP9 and CASP10) or different (CASP2) in the liver. For some caspases (CASP1, CASP6 and CASP7) these correlations could be related to brain aging.

Show MeSH
Related in: MedlinePlus