title: Partial Loss of Genomic Imprinting Reveals Important Roles for Kcnq1 and Peg10 Imprinted Domains in Placental Development.
abstract: Mutations in imprinted genes or their imprint control regions (ICRs) produce changes in imprinted gene expression and distinct abnormalities in placental structure, indicating the importance of genomic imprinting to placental development. We have recently shown that a very broad spectrum of placental abnormalities associated with altered imprinted gene expression occurs in the absence of the oocyte-derived DNMT1o cytosine methyltransferase, which normally maintains parent-specific imprinted methylation during preimplantation. The absence of DNMT1o partially reduces inherited imprinted methylation while retaining the genetic integrity of imprinted genes and their ICRs. Using this novel system, we undertook a broad and inclusive approach to identifying key ICRs involved in placental development by correlating loss of imprinted DNA methylation with abnormal placental phenotypes in a mid-gestation window (E12.5-E15.5). To these ends we measured DNA CpG methylation at 15 imprinted gametic differentially methylated domains (gDMDs) that overlap known ICRs using EpiTYPER-mass array technology, and linked these epigenetic measurements to histomorphological defects. Methylation of some imprinted gDMDs, most notably Dlk1, was nearly normal in mid-gestation DNMT1o-deficient placentas, consistent with the notion that cells having lost methylation on these DMDs do not contribute significantly to placental development. Most imprinted gDMDs however showed a wide range of methylation loss among DNMT1o-deficient placentas. Two striking associations were observed. First, loss of DNA methylation at the Peg10 imprinted gDMD associated with decreased embryonic viability and decreased labyrinthine volume. Second, loss of methylation at the Kcnq1 imprinted gDMD was strongly associated with trophoblast giant cell (TGC) expansion. We conclude that the Peg10 and Kcnq1 ICRs are key regulators of mid-gestation placental function.
authors.affiliation: Magee-Womens Research Institute, Program in Integrative Molecular Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Erik
authors.initials: E
authors.lastname: Koppes
authors.affiliation: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Himes
authors.affiliation: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: J Richard
authors.initials: JR
authors.lastname: Chaillet
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D005260:Female; D005313:Fetal Death / Q000209:etiology; D018392:Genomic Imprinting / Q000502:physiology*; D005865:Gestational Age; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000502:physiology*; D008098:Litter Size; D051379:Mice; D057507:Mice, 129 Strain; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D010920:Placenta / Q000002:abnormalities*; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse; D009687:Nuclear Proteins; C110780:Peg10 protein, mouse; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014280:Triglycerides; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse