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Epigenetic regulation of COX?2 expression by DNA hypomethylation via NF??B activation in ketamine?induced ulcerative cystitis.

ABSTRACT: The present study investigated the methylation of CpG sites in the cyclooxygenase (COX)?2 promoter via nuclear factor (NF)??B transcriptional regulation and elucidated its effect on the COX?2 transcriptional expression in a ketamine?induced ulcerative cystitis (KIC) animal model. The results of the present study revealed that ketamine treatment induced NF??B p65 translocation to nuclei and activated COX?2 expression and prostaglandin (PGE)2 production in bladder tissue, whereas COX?2 inhibitor suppressed the inflammatory effect. Moreover, DNA hypomethylation of the COX?2 promoter region located from ?1,522 to ?829 bp might contribute to transcriptional regulation of COX?2 expression and induce a pro?inflammatory response in KIC. Ketamine treatment increased the binding of NF??B and permissive histone H3 lysine?4 (H3K4)m3, but caused a decrease in the repressive histone H3K27m3 and H3K36m3 on the COX?2 promoter ranging from ?1,522 to ?1,331 bp as determined by a chromatin immunoprecipitation assay. Moreover, in the ketamine group, the level of Ten?Eleven?Translocation methylcytosine dioxygenase for demethylation as determined by reverse transcription?quantitative PCR assay was increased in comparison with the control group, but that was not the case for the level of DNA methyltransferases for methylation. The present findings revealed that there was a hypomethylation pattern of the COX?2 promoter in association with the level of COX?2 transcription in KIC.

SUBMITTER: Chuang SM

PROVIDER: S-EPMC6657979 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Epigenetic regulation of COX‑2 expression by DNA hypomethylation via NF‑κB activation in ketamine‑induced ulcerative cystitis.

Chuang Shu-Mien SM Lu Jian-He JH Lin Kun-Ling KL Long Cheng-Yu CY Lee Yung-Chin YC Hsiao Hui-Pin HP Tsai Chia-Chun CC Wu Wen-Jeng WJ Yang Hui-Jun HJ Juan Yung-Shun YS

International journal of molecular medicine 20190621 3

The present study investigated the methylation of CpG sites in the cyclooxygenase (COX)‑2 promoter via nuclear factor (NF)‑κB transcriptional regulation and elucidated its effect on the COX‑2 transcriptional expression in a ketamine‑induced ulcerative cystitis (KIC) animal model. The results of the present study revealed that ketamine treatment induced NF‑κB p65 translocation to nuclei and activated COX‑2 expression and prostaglandin (PGE)2 production in bladder tissue, whereas COX‑2 inhibitor s ...[more]

PMID: 31257475

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Project description:Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by neurotropic polyomavirus, JC virus (JCV), a virus that causes lytic infection of CNS glial cells. After primary infection, JCV is controlled by the immune system but virus persists asymptomatically. Rarely, when immune function is impaired, it can reemerge to cause PML. The mechanisms of JCV persistence and reactivation are not well understood but our earlier work implicated epigenetic control by protein acetylation since histone deacetylase inhibitors such as trichostatin A (TSA) strongly stimulate JCV transcription. Since both TNF-α and TSA activate JCV transcription via the same unique NF-κB site in the JCV control region, we investigated a role for acetylation of NF-κB in JCV regulation. A site-directed mutagenesis strategy was employed targeting the known lysine acetylation sites of NF-κB p65: K218, K221, and K310. We individually mutated each lysine to arginine, which cannot be acetylated and retains a positive charge like lysine. K218R and K221R impaired transactivation of JCV early promoter transcription either alone or combined with TSA treatment or coexpression of acetyltransferase transcriptional coactivator p300 but K310R was largely without effect. Mutation of lysine to glutamine gives mutants with a negative charge like acetyllysine. However, K218Q and K221Q showed impaired activity and only K310Q showed enhanced transactivation. NF-κB acetylation can regulate several aspects of the process of activation including complex formation with IκB, translocation to the nucleus, and DNA binding and transcriptional activation. Cell fractionation studies revealed that the mutants had no defect in translocation to the nucleus whereas gel shift studies revealed reduced binding to the JCV NF-κB site. Thus, acetylation regulates NF-κB p65 activity toward JCV at the level of p65 binding to the JCV control region and activation of JCV transcription.

Dataset Information

Epigenetic regulation of COX?2 expression by DNA hypomethylation via NF??B activation in ketamine?induced ulcerative cystitis.

Publications

Epigenetic regulation of COX‑2 expression by DNA hypomethylation via NF‑κB activation in ketamine‑induced ulcerative cystitis.

Similar Datasets

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