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Hypo-CpG methylation controls PTEN expression and cell apoptosis in irradiated lung.

ABSTRACT: The current study was designed to address our hypothesis that oxidative stress secondary to the ionizing event upregulates phosphatase and tensin homolog (PTEN) mRNA and protein in the lungs of C57BL/6J mice through oxidative DNA damage resulting in CpG hypomethylation in the PTEN promoter.Fibrosis-prone C57BL/6J mice were exposed to 0 or 15 Gy of 320 kVp X-rays to the whole thorax. Lung tissue was serially harvested at time points between one day and six months postirradiation. Tissue levels of PTEN mRNA, total protein, and phosphorylated PTEN, as well as CpG methylation of the PTEN promoter, expression of DNA methyltransferases 1 (Dnmt1) and 3a (Dnmt3a), NADPH oxidase 4 (Nox4) protein expression, and DNA damage levels were measured. The induction of DNA damage and global methylation changes were also examined in hydrogen peroxide (H2O2)-treated human umbilical vein endothelial cells (HUVECs) and human bronchial epithelial cells in vitro.These experiments demonstrate that PTEN mRNA and protein, Nox4 protein, and DNA damage levels increase continuously from one day to six months following radiation exposure. Elevated PTEN transcription and translation are likely the result of the observed decrease in CpG methylation of the PTEN promoter region. This finding is not consistent with the observed increase in Dnmt1 and Dnmt3a protein expression, implicating an alternative mechanism as the driving force behind hypomethylation. In vitro results provide evidence that H2O2 can induce DNA damage and affect DNA methylation status. The Mn porphyrin-based superoxide dismutase (SOD) mimic MnTnHEx-2-PyP(5+ )exhibited partial rescue from radiation-induced hypomethylation.Taken together, these data suggest that reactive oxygen species (ROS)-induced DNA damage results in hypomethylation of the PTEN promoter, upregulation of PTEN mRNA and protein, and a subsequent increase in apoptosis in irradiated lung tissue.

SUBMITTER: Zhang X

PROVIDER: S-EPMC6121701 | biostudies-other | 2016 Aug

REPOSITORIES: biostudies-other

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Hypo-CpG methylation controls PTEN expression and cell apoptosis in irradiated lung.

Zhang Xiuwu X Hadley Caroline C Jackson Isabel L IL Zhang Yi Y Zhang Angel A Spasojevic Ivan I Haberle Ines Batinic IB Vujaskovic Zeljko Z

Free radical research 20160701 8

<h4>Purpose</h4>The current study was designed to address our hypothesis that oxidative stress secondary to the ionizing event upregulates phosphatase and tensin homolog (PTEN) mRNA and protein in the lungs of C57BL/6J mice through oxidative DNA damage resulting in CpG hypomethylation in the PTEN promoter.<h4>Methods</h4>Fibrosis-prone C57BL/6J mice were exposed to 0 or 15 Gy of 320 kVp X-rays to the whole thorax. Lung tissue was serially harvested at time points between one day and six months p ...[more]

PMID: 27367846

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Project description:DNA methylation of retroviral promoters and enhancers localized in the provirus 5' long terminal repeat (LTR) is considered to be a mechanism of transcriptional suppression that allows retroviruses to evade host immune responses and antiretroviral drugs. However, the role of DNA methylation in the control of HIV-1 latency has never been unambiguously demonstrated, in contrast to the apparent importance of transcriptional interference and chromatin structure, and has never been studied in HIV-1-infected patients. Here, we show in an in vitro model of reactivable latency and in a latent reservoir of HIV-1-infected patients that CpG methylation of the HIV-1 5' LTR is an additional epigenetic restriction mechanism, which controls resistance of latent HIV-1 to reactivation signals and thus determines the stability of the HIV-1 latency. CpG methylation acts as a late event during establishment of HIV-1 latency and is not required for the initial provirus silencing. Indeed, the latent reservoir of some aviremic patients contained high proportions of the non-methylated 5' LTR. The latency controlled solely by transcriptional interference and by chromatin-dependent mechanisms in the absence of significant promoter DNA methylation tends to be leaky and easily reactivable. In the latent reservoir of HIV-1-infected individuals without detectable plasma viremia, we found HIV-1 promoters and enhancers to be hypermethylated and resistant to reactivation, as opposed to the hypomethylated 5' LTR in viremic patients. However, even dense methylation of the HIV-1 5'LTR did not confer complete resistance to reactivation of latent HIV-1 with some histone deacetylase inhibitors, protein kinase C agonists, TNF-alpha, and their combinations with 5-aza-2deoxycytidine: the densely methylated HIV-1 promoter was most efficiently reactivated in virtual absence of T cell activation by suberoylanilide hydroxamic acid. Tight but incomplete control of HIV-1 latency by CpG methylation might have important implications for strategies aimed at eradicating HIV-1 infection.

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Hypo-CpG methylation controls PTEN expression and cell apoptosis in irradiated lung.

Publications

Hypo-CpG methylation controls PTEN expression and cell apoptosis in irradiated lung.

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