title: Loss of inherited genomic imprints in mice leads to severe disruption in placental lipid metabolism.
abstract: BACKGROUND
  Monoallelic expression of imprinted genes is necessary for placental development and normal fetal growth. Differentially methylated domains (DMDs) largely determine the parental-specific monoallelic expression of imprinted genes. Maternally derived DNA (cytosine-5-) -methyltransferase 1o (DNMT1o) maintains DMDs during the eight-cell stage of development. DNMT1o-deficient mouse placentas have a generalized disruption of genomic imprints. Previous studies have demonstrated that DNMT1o deficiency alters placental morphology and broadens the embryonic weight distribution in late gestation. Lipids are critical for fetal growth. Thus, we assessed the impact of disrupted imprinting on placental lipids.
  
  
  METHODS
  Lipids were quantified from DNMT1o-deficient mouse placentas and embryos at E17.5 using a modified Folch method. Expression of select genes critical for lipid metabolism was quantified with RT-qPCR. Mitochondrial morphology was assessed by TEM and mitochondrial aconitase and cytoplasmic citrate concentrations quantified. DMD methylation was determined by EpiTYPER.
  
  
  RESULTS
  We found that DNMT1o deficiency is associated with increased placental triacylglycerol levels. Neither fetal triacylglycerol concentrations nor expression of select genes that mediate placental lipid transport were different from wild type. Placental triacylglycerol accumulation was associated with impaired beta-oxidation and abnormal citrate metabolism with decreased mitochondrial aconitase activity and increased cytoplasmic citrate concentrations. Loss of methylation at the MEST DMD was strongly associated with placental triacylglycerol accumulation.
  
  
  CONCLUSIONS
  A generalized disruption of genomic imprints leads to triacylglycerol accumulation and abnormal mitochondrial function. This could stem directly from a loss of methylation at a given DMD, such as MEST, or represent a consequence of abnormal placental development.
authors: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA 15213, USA. Electronic address: himekp@upmc.edu.
authors: K P
authors: KP
authors: Himes
authors: Magee-Womens Research Institute, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA 15213, USA. Electronic address: alexandria.n.young@gmail.com.
authors: A
authors: A
authors: Young
authors: Magee-Womens Research Institute, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA 15213, USA. Electronic address: koppesea@mwri.magee.edu.
authors: E
authors: E
authors: Koppes
authors: Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: dstolz@pitt.edu.
authors: D
authors: D
authors: Stolz
authors: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA 15213, USA; Magee-Womens Research Institute, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA 15213, USA. Electronic address: baraky@mwri.magee.edu.
authors: Y
authors: Y
authors: Barak
authors: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA 15213, USA; Magee-Womens Research Institute, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA 15213, USA. Electronic address: ysadovsky@mwri.magee.edu.
authors: Y
authors: Y
authors: Sadovsky
authors: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA 15213, USA. Electronic address: chailletjr@mwri.magee.edu.
authors: J R
authors: JR
authors: Chaillet
mesh_terms: D000154:Aconitate Hydratase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019343:Citric Acid / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004622:Embryo, Mammalian / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology*; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D050356:Lipid Metabolism; D008297:Male; D057507:Mice, 129 Strain; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D010920:Placenta / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D010922:Placenta Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D014280:Triglycerides / Q000096:biosynthesis
chemical_list: D014280:Triglycerides; D019343:Citric Acid; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; D000154:Aconitate Hydratase
keywords: DNMT1; Genomic imprinting; Lipids; Mitochondria; Triacylglycerols