title: Epigenetic upregulation of large-conductance Ca2+-activated K+ channel expression in uterine vascular adaptation to pregnancy.
abstract: Our previous study demonstrated that pregnancy increased large-conductance Ca(2+)-activated potassium channel β1 subunit (BKβ1) expression and large-conductance Ca(2+)-activated potassium channel activity in uterine arteries, which were abrogated by chronic hypoxia. The present study tested the hypothesis that promoter methylation/demethylation is a key mechanism in epigenetic reprogramming of BKβ1 expression patterns in uterine arteries. Ovine BKβ1 promoter of 2315 bp spanning from -2211 to +104 of the transcription start site was cloned, and an Sp1-380 binding site that contains CpG dinucleotide in its core binding sequences was identified. Site-directed deletion of the Sp1 site significantly decreased the BKβ1 promoter activity. Estrogen receptor-α bound to the Sp1 site through tethering to Sp1 and upregulated the expression of BKβ1. The Sp1 binding site at BKβ1 promoter was highly methylated in uterine arteries of nonpregnant sheep, and methylation inhibited transcription factor binding and BKβ1 promoter activity. Pregnancy caused a significant decrease in CpG methylation at the Sp1 binding site and increased Sp1 binding to the BKβ1 promoter and BKβ1 mRNA abundance. Chronic hypoxia during gestation abrogated this pregnancy-induced demethylation and upregulation of BKβ1 expression. The results provide evidence of a novel mechanism of promoter demethylation in pregnancy-induced reprogramming of large-conductance Ca(2+)-activated potassium channel expression and function in uterine arteries and suggest new insights of epigenetic mechanisms linking gestational hypoxia to aberrant uteroplacental circulation and increased risk of preeclampsia.
authors.affiliation: From the Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA.
authors.forename: Man
authors.initials: M
authors.lastname: Chen
authors.affiliation: From the Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA.
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Dasgupta
authors.affiliation: From the Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA.
authors.forename: Fuxia
authors.initials: F
authors.lastname: Xiong
authors.affiliation: From the Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, CA. lzhang@llu.edu.
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D018899:CpG Islands / Q000235:genetics / Q000502:physiology; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics / Q000502:physiology*; D023421:Models, Animal; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D011268:Pregnancy-Specific beta 1-Glycoproteins / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D012756:Sheep; D015854:Up-Regulation; D055988:Uterine Artery / Q000502:physiology*
chemical_list: D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D011268:Pregnancy-Specific beta 1-Glycoproteins
keywords: BKCa channel; epigenomics; hypoxia; pregnancy