title: In utero exposure to a maternal high-fat diet alters the epigenetic histone code in a murine model.
abstract: OBJECTIVE
  Data from animal models show that in utero exposure to a maternal high-fat diet (HFD) renders susceptibility of these offspring to the adult onset of metabolic syndrome. We and others have previously shown that epigenetic modifications to histones may serve as a molecular memory of the in utero exposure, rendering the risk of adult disease. Because mice heterozygous for the Glut4 gene (insulin sensitive glucose transporter) born to wild-type (WT) mothers demonstrate exacterbated metabolic syndrome when exposed to an HFD in utero, we sought to analyze the genome-wide epigenetic changes that occur in the fetal liver in susceptible offspring.
  
  
  METHODS
  WT and Glut4(+/-) (G4(+/-)) offspring of WT mothers that were exposed either to a control or an HFD in utero were studied. Immunoblotting was used to measure hepatic histone modifications of fetal and 5-week animals. Chromatin immunoprecipitation (ChIP) followed by hybridization to chip arrays (ChIP-on-chip) was used to detect genome-wide changes of histone modifications with HFD exposure.
  
  
  RESULTS
  We found that levels of hepatic H3K14ac and H3K9me3 significantly increased with HFD exposure in WT and G4(+/-) fetal and 5-week offspring. Pathway analysis of our ChIP-on-chip data revealed differential H3K14ac and H3K9me3 enrichment along pathways that regulate lipid metabolism, specifically in the promoter regions of Pparg, Ppara, Rxra, and Rora.
  
  
  CONCLUSIONS
  We conclude that HFD exposure in utero is associated with functional alterations to fetal hepatic histone modifications in both WT and G4(+/-) offspring, some of which persist up to 5 weeks of age.
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Suter
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY; Division of Pediatric Endocrinology, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Vuguin
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hartil
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Ariana
authors.initials: A
authors.lastname: Fiallo
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX.
authors.forename: R Alan
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY; Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Charron
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX. Electronic address: aagaardt@bcm.tmc.edu.
authors.forename: Kjersti M
authors.initials: KM
authors.lastname: Aagaard
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D055028:Comparative Genomic Hybridization; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D051275:Glucose Transporter Type 4 / Q000235:genetics; D042421:Histone Code / Q000187:drug effects* / Q000235:genetics; D006657:Histones / Q000235:genetics*; D008099:Liver / Q000196:embryology* / Q000201:enzymology; D024821:Metabolic Syndrome / Q000235:genetics; D051379:Mice; D023421:Models, Animal; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D039401:Prenatal Nutritional Physiological Phenomena / Q000235:genetics*
chemical_list: D004041:Dietary Fats; D051275:Glucose Transporter Type 4; D006657:Histones; C495693:Slc2a4 protein, mouse
keywords: GLUT4; H3K14ac; H3K9me3; developmental origin