title: Antenatal hypoxia induces epigenetic repression of glucocorticoid receptor and promotes ischemic-sensitive phenotype in the developing heart.
abstract: Large studies in humans and animals have demonstrated a clear association of an adverse intrauterine environment with an increased risk of cardiovascular disease later in life. Yet mechanisms remain largely elusive. The present study tested the hypothesis that gestational hypoxia leads to promoter hypermethylation and epigenetic repression of the glucocorticoid receptor (GR) gene in the developing heart, resulting in increased heart susceptibility to ischemia and reperfusion injury in offspring. Hypoxic treatment of pregnant rats from day 15 to 21 of gestation resulted in a significant decrease of GR exon 14, 15, 16, and 17 transcripts, leading to down-regulation of GR mRNA and protein in the fetal heart. Functional cAMP-response elements (CREs) at -4408 and -3896 and Sp1 binding sites at -3425 and -3034 were identified at GR untranslated exon 1 promoters. Hypoxia significantly increased CpG methylation at the CREs and Sp1 binding sites and decreased transcription factor binding to GR exon 1 promoter, accounting for the repression of the GR gene in the developing heart. Of importance, treatment of newborn pups with 5-aza-2'-deoxycytidine reversed hypoxia-induced promoter methylation, restored GR expression and prevented hypoxia-mediated increase in ischemia and reperfusion injury of the heart in offspring. The findings demonstrate a novel mechanism of epigenetic repression of the GR gene in fetal stress-mediated programming of ischemic-sensitive phenotype in the heart.
authors.affiliation: Institute for Fetology and Reproductive Medicine Center, First Hospital of Soochow University, Suzhou, China; Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Fuxia
authors.initials: F
authors.lastname: Xiong
authors.affiliation: Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Thant
authors.initials: T
authors.lastname: Lin
authors.affiliation: Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Minwoo
authors.initials: M
authors.lastname: Song
authors.affiliation: Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Shannalee R
authors.initials: SR
authors.lastname: Martinez
authors.affiliation: Institute for Fetology and Reproductive Medicine Center, First Hospital of Soochow University, Suzhou, China; Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Juanxiu
authors.initials: J
authors.lastname: Lv
authors.affiliation: Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: MataGreenwood
authors.affiliation: Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Daliao
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Institute for Fetology and Reproductive Medicine Center, First Hospital of Soochow University, Suzhou, China; Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
authors.forename: Zhice
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Institute for Fetology and Reproductive Medicine Center, First Hospital of Soochow University, Suzhou, China; Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA. Electronic address: lzhang@llu.edu.
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001665:Binding Sites; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D044127:Epigenesis, Genetic; D005091:Exons; D005260:Female; D000860:Hypoxia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018811:Maternal Exposure; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010100:Oxygen / Q000494:pharmacology*; D010641:Phenotype; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D016329:Sp1 Transcription Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D011965:Receptors, Glucocorticoid; D016329:Sp1 Transcription Factor; D000077209:Decitabine; D001374:Azacitidine; D010100:Oxygen
keywords: DNA methylation; Fetal programming; Glucocorticoid receptor; Hypoxia