title: Enhanced trimethylation of histone h3 mediates impaired expression of hepatic glucose 6-phosphatase expression in offspring from rat dams exposed to hypoxia during pregnancy.
abstract: Given that hepatic glucose 6-phosphatase (G6Pase, involved in gluconeogenesis) has been demonstrated to be altered long term in animal models of intrauterine growth restriction (IUGR), we hypothesized that hypoxia in utero may regulate G6Pase expression via epigenetic mechanisms. To address this further, a rat model of maternal hypoxia leading to IUGR and impaired liver growth was utilized. In the 12-month-old male offspring of pregnant rat dams exposed to 11.5% atmospheric oxygen from gestational day (gd) 15 to gd 21, nonfasting glucose was lower in association with decreased hepatic G6Pase messenger RNA and protein levels. This was concomitant with enhanced methylation of histone H3 [K9] surrounding the promoter of G6Pase. Moreover, when McA-RH7777 hepatoma cells were exposed to various concentrations of oxygen for 48 hours, we observed an oxygen-dependent decrease in G6Pase expression associated with enhanced histone H3 [K9] methylation. Collectively, these results indicate that hypoxia directly and indirectly impairs G6Pase expression through enhanced methylation of histone H3 [K9].
authors.affiliation: 1The Department of Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Osumek
authors.forename: Andrew
authors.initials: A
authors.lastname: Revesz
authors.forename: Jude S
authors.initials: JS
authors.lastname: Morton
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Hardy
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000254:growth & development; D008297:Male; D008745:Methylation; D010100:Oxygen / Q000378:metabolism*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D005952:Glucose-6-Phosphatase; C582554:Pck1 protein, rat; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D010100:Oxygen
keywords: fetal programming; glucose 6-phosphatase; hypoxia; liver; posttranslational histone modifications