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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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Analysis of LIPA and caspases expression in GBM and different areas of the CNS.A. Plot of CASP2 versus LIPA expression levels in GBM. Linear regression is reported. B. Correlations in expression levels between LIPA and the indicated genes in GBM. C. Correlations in expression levels between LIPA and the indicated genes in different CNS areas.
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pone-0110610-g003: Analysis of LIPA and caspases expression in GBM and different areas of the CNS.A. Plot of CASP2 versus LIPA expression levels in GBM. Linear regression is reported. B. Correlations in expression levels between LIPA and the indicated genes in GBM. C. Correlations in expression levels between LIPA and the indicated genes in different CNS areas.

Mentions: Taking into account the complex regulative networks influencing cholesterol homeostasis in vivo, the use of the cell culture models to investigate correlations between caspase-2 and cholesterol genes expression is limiting. Hence, to further expand our study we decided to interrogate public available gene expression datasets of glioblastomas. In principle, if caspase-2 controls a circuit that influence LIPA expression in cultured glioblastoma cells the expression of these two genes should be inversely correlated in tumors. Gene expression profiles from 13 datasets including 327 microarrays of GBM were interrogated. Figure 3A illustrates that in glioblastoma, mRNA levels for CASP2 and LIPA evidence a weak, but significant inverse Pearson correlation (r -0.2593; p-value 2.00E-00.6).


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)

Analysis of LIPA and caspases expression in GBM and different areas of the CNS.A. Plot of CASP2 versus LIPA expression levels in GBM. Linear regression is reported. B. Correlations in expression levels between LIPA and the indicated genes in GBM. C. Correlations in expression levels between LIPA and the indicated genes in different CNS areas.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110610-g003: Analysis of LIPA and caspases expression in GBM and different areas of the CNS.A. Plot of CASP2 versus LIPA expression levels in GBM. Linear regression is reported. B. Correlations in expression levels between LIPA and the indicated genes in GBM. C. Correlations in expression levels between LIPA and the indicated genes in different CNS areas.
Mentions: Taking into account the complex regulative networks influencing cholesterol homeostasis in vivo, the use of the cell culture models to investigate correlations between caspase-2 and cholesterol genes expression is limiting. Hence, to further expand our study we decided to interrogate public available gene expression datasets of glioblastomas. In principle, if caspase-2 controls a circuit that influence LIPA expression in cultured glioblastoma cells the expression of these two genes should be inversely correlated in tumors. Gene expression profiles from 13 datasets including 327 microarrays of GBM were interrogated. Figure 3A illustrates that in glioblastoma, mRNA levels for CASP2 and LIPA evidence a weak, but significant inverse Pearson correlation (r -0.2593; p-value 2.00E-00.6).

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