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Pregnancy Reprograms Large-Conductance Ca2+-Activated K+ Channel in Uterine Arteries: Roles of Ten-Eleven Translocation Methylcytosine Dioxygenase 1-Mediated Active Demethylation.

ABSTRACT: The large-conductance Ca2+-activated K+ (BKCa) channel is of critical importance in pregnancy-mediated increase in uterine artery vasodilation and blood flow. The present study tested the hypothesis that active DNA demethylation plays a key role in pregnancy-induced reprogramming and upregulation of BKCa channel ?1 subunit (BK?1) in uterine arteries. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep. Pregnancy significantly increased the expression of ten-eleven translocation methylcytosine dioxygenase 1 (TET1) in uterine arteries. A half-palindromic estrogen response element was identified at the TET1 promoter, and estrogen treatment increased TET1 promoter activity and TET1 expression in uterine arteries. In accordance, pregnancy and steroid hormone treatment resulted in demethylation of BK?1 promoter by increasing 5-hydroxymethylcytosine and decreasing 5-methylcytosine at the CpG in the Sp1-380 binding site that is of critical importance in the regulation of the promoter activity and BK?1 expression. Inhibition of TET1 with fumarate significantly decreased BK?1 expression in uterine arteries of pregnant animals and blocked steroid hormone-induced upregulation of BK?1. Functionally, fumarate treatment inhibited pregnancy and steroid hormone-induced increases in BKCa channel current density and BKCa channel-mediated relaxations. In addition, fumarate blocked pregnancy and steroid hormone-induced decrease in pressure-dependent myogenic tone of the uterine artery. The results demonstrate a novel mechanism of estrogen-mediated active DNA demethylation in reprogramming of BKCa channel expression and function in the adaption of uterine circulation during pregnancy.

SUBMITTER: Hu XQ

PROVIDER: S-EPMC5426984 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Pregnancy Reprograms Large-Conductance Ca2+-Activated K+ Channel in Uterine Arteries: Roles of Ten-Eleven Translocation Methylcytosine Dioxygenase 1-Mediated Active Demethylation.

Hu Xiang-Qun XQ Dasgupta Chiranjib C Chen Man M Xiao Daliao D Huang Xiaohui X Han Limin L Yang Shumei S Xu Zhice Z Zhang Lubo L

Hypertension (Dallas, Tex. : 1979) 20170410 6

The large-conductance Ca2+-activated K+ (BKCa) channel is of critical importance in pregnancy-mediated increase in uterine artery vasodilation and blood flow. The present study tested the hypothesis that active DNA demethylation plays a key role in pregnancy-induced reprogramming and upregulation of BKCa channel β1 subunit (BKβ1) in uterine arteries. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep. Pregnancy significantly i ...[more]

PMID: 28396535

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Project description:Liver-specific ten-eleven translocation (Tet) methylcytosine dioxygenases 2 and 3 (Tet2 plus Tet3)-deficient hepatitis B virus (HBV) transgenic mice fail to support viral biosynthesis. The levels of viral transcription and replication intermediates are dramatically reduced. Hepatitis B core antigen is only observed in a very limited number of pericentral hepatocytes in a pattern that is similar to glutamate-ammonia ligase (Glul), a β-catenin target gene. HBV transcript abundance in adult Tet-deficient mice resembles that observed in wild-type neonatal mice. Furthermore, the RNA levels of several β-catenin target genes including Glul, Lhpp, Notun, Oat, Slc1a2, and Tbx3 in Tet-deficient mice were also similar to that observed in wild-type neonatal mice. As HBV transcription is regulated by β-catenin, these findings support the suggestion that neonatal Tet deficiency might limit β-catenin target gene expression, limiting viral biosynthesis. Additionally, HBV transgene DNA displays increased 5-methylcytosine (5mC) frequency at CpG sequences consistent with neonatal Tet deficiency being responsible for decreased developmental viral DNA demethylation mediated by 5mC oxidation to 5-hydroxymethylcytosine, a process that might be responsible for the reduction in cellular β-catenin target gene expression and viral transcription and replication.IMPORTANCEChronic hepatitis B virus (HBV) infection causes significant worldwide morbidity and mortality. There are no curative therapies available to resolve chronic HBV infections, and the small viral genome limits molecular targets for drug development. An alternative approach to drug development is to target cellular genes essential for HBV biosynthesis. In the liver, ten-eleven translocation (Tet) genes encode cellular enzymes that are not essential for postnatal mouse development but represent essential activities for viral DNA demethylation and transcription. Consequently, Tet inhibitors may potentially be developed into therapeutic agents capable of inducing and/or maintaining HBV covalently closed circular DNA methylation, resulting in transcriptional silencing and the resolution of chronic viral infection.

Project description:BackgroundThe nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in dorsal root ganglion (DRG) contributes to pain hypersensitivity in multiple neuropathic pain models, but the function of the NLRP3 in diabetic neuropathic pain (DNP) and the regulation mechanism are still largely unknown. Epigenetic regulation plays a vital role in the controlling of gene expression. Ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is a DNA demethylase that contributes to transcriptional activation. TET2 is also involved in high glucose (HG)-induced pathology.MethodsDNP was induced in mice via the intraperitoneal injection of streptozotocin (STZ) for five consecutive days and the mechanical threshold was evaluated in STZ-diabetic mice by using von Frey hairs. The expression level of the NLRP3 pathway and TET2 in DRG were determined through molecular biology experiments. The regulation of the NLRP3 pathway by TET2 was examined in in vitro and in vivo conditions.ResultsIn the present research, we first established the DNP model and found that NLRP3 pathway was activated in DRG. The treatment of NLRP3 inhibitor MCC950 alleviated the mechanical allodynia of DNP mice. Then we revealed that in STZ-diabetic mice DRG, the genomic DNA was demethylated, and the expression of DNA demethylase TET2 was increased evidently. Using RNA-sequencing analysis, we found that the expression of Txnip, a gene that encodes a thioredoxin-interacting protein (TXNIP) which mediates NLRP3 activation, was elevated in the DRG after STZ treatment. In addition, knocking down of TET2 expression in DRG using TET2-siRNA suppressed the mRNA expression of Txnip and subsequently inhibited the expression/activation of NLRP3 inflammasome in vitro and in vivo as well as relieved the pain sensitivity of DNP animals.ConclusionThe results suggested that the upregulation of the TXNIP/NLRP3 pathway by TET2 in DRG was involved in the pain hypersensitivity of the DNP model.

Dataset Information

Pregnancy Reprograms Large-Conductance Ca2+-Activated K+ Channel in Uterine Arteries: Roles of Ten-Eleven Translocation Methylcytosine Dioxygenase 1-Mediated Active Demethylation.

Publications

Pregnancy Reprograms Large-Conductance Ca<sup>2+</sup>-Activated K<sup>+</sup> Channel in Uterine Arteries: Roles of Ten-Eleven Translocation Methylcytosine Dioxygenase 1-Mediated Active Demethylation.

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