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Hypomethylation of the promoter of the catalytic subunit of protein phosphatase 2A in response to hyperglycemia.

ABSTRACT: In order to identify epigenetic mechanisms through which hyperglycemia can affect gene expression durably in ? cells, we screened DNA methylation changes induced by high glucose concentrations (25 mmol/L) in the BTC3 murine cell line, using an epigenome-wide approach. Exposure of BTC3 cells to high glucose modified the expression of 1612 transcripts while inducing significant methylation changes in 173 regions. Among these 173 glucose-sensitive differentially methylated regions (DMRs), 14 were associated with changes in gene expression, suggesting an epigenetic effect of high glucose on gene transcription at these loci. Among these 14 DMRs, we selected for further study Pp2ac, a gene previously suspected to play a role in ?-cell physiology and type 2 diabetes. Using RT-qPCR and bisulfite pyrosequencing, we confirmed our previous observations in BTC3 cells and found that this gene was significantly demethylated in the whole blood cells (WBCs) of type 2 diabetic patients compared to controls.

SUBMITTER: Tros F

PROVIDER: S-EPMC4187575 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Hypomethylation of the promoter of the catalytic subunit of protein phosphatase 2A in response to hyperglycemia.

Tros Fabiola F Meirhaeghe Aline A Hadjadj Samy S Amouyel Philippe P Bougnères Pierre P Fradin Delphine D

Physiological reports 20140716 7

In order to identify epigenetic mechanisms through which hyperglycemia can affect gene expression durably in β cells, we screened DNA methylation changes induced by high glucose concentrations (25 mmol/L) in the BTC3 murine cell line, using an epigenome-wide approach. Exposure of BTC3 cells to high glucose modified the expression of 1612 transcripts while inducing significant methylation changes in 173 regions. Among these 173 glucose-sensitive differentially methylated regions (DMRs), 14 were a ...[more]

PMID: 25347859

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Project description:UnlabelledThe generation of complex three-dimensional structures is a key developmental step for most eukaryotic organisms. The details of the molecular machinery controlling this step remain to be determined. An excellent model system to study this general process is the generation of three-dimensional fruiting bodies in filamentous fungi like Sordaria macrospora Fruiting body development is controlled by subunits of the highly conserved striatin-interacting phosphatase and kinase (STRIPAK) complex, which has been described in organisms ranging from yeasts to humans. The highly conserved heterotrimeric protein phosphatase PP2A is a subunit of STRIPAK. Here, catalytic subunit 1 of PP2A was functionally characterized. The Δpp2Ac1 strain is sterile, unable to undergo hyphal fusion, and devoid of ascogonial septation. Further, PP2Ac1, together with STRIPAK subunit PRO22, governs vegetative and stress-related growth. We revealed in vitro catalytic activity of wild-type PP2Ac1, and our in vivo analysis showed that inactive PP2Ac1 blocks the complementation of the sterile deletion strain. Tandem affinity purification, followed by mass spectrometry and yeast two-hybrid analysis, verified that PP2Ac1 is a subunit of STRIPAK. Further, these data indicate links between the STRIPAK complex and other developmental signaling pathways, implying the presence of a large interconnected signaling network that controls eukaryotic developmental processes. The insights gained in our study can be transferred to higher eukaryotes and will be important for understanding eukaryotic cellular development in general.ImportanceThe striatin-interacting phosphatase and kinase (STRIPAK) complex is highly conserved from yeasts to humans and is an important regulator of numerous eukaryotic developmental processes, such as cellular signaling and cell development. Although functional insights into the STRIPAK complex are accumulating, the detailed molecular mechanisms of single subunits are only partially understood. The first fungal STRIPAK was described in Sordaria macrospora, which is a well-established model organism used to study the formation of fungal fruiting bodies, three-dimensional organ-like structures. We analyzed STRIPAK subunit PP2Ac1, catalytic subunit 1 of protein phosphatase PP2A, to study the importance of the catalytic activity of this protein during sexual development. The results of our yeast two-hybrid analysis and tandem affinity purification, followed by mass spectrometry, indicate that PP2Ac1 activity connects STRIPAK with other signaling pathways and thus forms a large interconnected signaling network.

Dataset Information

Hypomethylation of the promoter of the catalytic subunit of protein phosphatase 2A in response to hyperglycemia.

Publications

Hypomethylation of the promoter of the catalytic subunit of protein phosphatase 2A in response to hyperglycemia.

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