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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: 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.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.

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 brain and GBM.Correlations in terms of expression levels between caspases and cholesterol genes in different brain and GBM 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-g005: Co-expression analysis of caspases and cholesterol genes in human brain and GBM.Correlations in terms of expression levels between caspases and cholesterol genes in different brain and GBM 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: Almost all the cholesterol found in the CNS is produced from local biosynthesis [52]. Also in the case of the category “cholesterol biosynthesis”, correlation analysis revealed that the regulative apoptotic caspases, with the addition of CASP1 cluster together. In particular strong positive correlations (Fig. 5 and Table S3) with mRNA levels of a group of genes involved in cholesterol biosynthesis (LSS, CYB5R3, DHCR7, MVK) emerged. By contrast, HMGCR the gene encoding for the enzyme converting the 3-hydroxyl-3-methyl-glutarylCoA (HMG-CoA) into mevalonate scores a good but negative correlation. Since it represents the limiting step in cholesterol biosynthesis, the implications of the correlations between certain enzymes of cholesterol biosynthesis and regulative apoptotic caspases are unclear at the moment. Significant correlations were not observed for all the other caspases. Expression of CYP51A1 in the brain achieves a strong inverse correlation compared to CASP2, CASP9 and CASP10. CYP51A1 encodes for lanosterol 14α-demethylase, which in addition to being a key enzyme of the cholesterol biosynthetic pathway [31] is also involved in the steroidogenesis [53].


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 brain and GBM.Correlations in terms of expression levels between caspases and cholesterol genes in different brain and GBM 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-g005: Co-expression analysis of caspases and cholesterol genes in human brain and GBM.Correlations in terms of expression levels between caspases and cholesterol genes in different brain and GBM 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: Almost all the cholesterol found in the CNS is produced from local biosynthesis [52]. Also in the case of the category “cholesterol biosynthesis”, correlation analysis revealed that the regulative apoptotic caspases, with the addition of CASP1 cluster together. In particular strong positive correlations (Fig. 5 and Table S3) with mRNA levels of a group of genes involved in cholesterol biosynthesis (LSS, CYB5R3, DHCR7, MVK) emerged. By contrast, HMGCR the gene encoding for the enzyme converting the 3-hydroxyl-3-methyl-glutarylCoA (HMG-CoA) into mevalonate scores a good but negative correlation. Since it represents the limiting step in cholesterol biosynthesis, the implications of the correlations between certain enzymes of cholesterol biosynthesis and regulative apoptotic caspases are unclear at the moment. Significant correlations were not observed for all the other caspases. Expression of CYP51A1 in the brain achieves a strong inverse correlation compared to CASP2, CASP9 and CASP10. CYP51A1 encodes for lanosterol 14α-demethylase, which in addition to being a key enzyme of the cholesterol biosynthetic pathway [31] is also involved in the steroidogenesis [53].

Bottom Line: 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.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.

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