title: Altered expression of the imprinted transcription factor PLAGL1 deregulates a network of genes in the human IUGR placenta.
abstract: Genomic imprinting is the epigenetic process that results in monoallelic expression of genes depending on parental origin. These genes are known to be critical for placental development and fetal growth in mammals. Aberrant epigenetic profiles at imprinted loci, such as DNA methylation defects, are surprisingly rare in pregnancies with compromised fetal growth, while variations in transcriptional output from the expressed alleles of imprinted genes are more commonly reported in pregnancies complicated with intrauterine growth restriction (IUGR). To determine if PLAGL1 and HYMAI, two imprinted transcripts deregulated in Transient Neonatal Diabetes Mellitus, are involved in non-syndromic IUGR we compared the expression and DNA methylation levels in a large cohort of placental biopsies from IUGR and uneventful pregnancies. This revealed that despite appropriate maternal methylation at the shared PLAGL1/HYMAI promoter, there was a loss of correlation between PLAGL1 and HYMAI expression in IUGR. This incongruity was due to higher HYMAI expression in IUGR gestations, coupled with PLAGL1 down-regulation in placentas from IUGR girls, but not boys. The PLAGL1 protein is a zinc-finger transcription factor that has been shown to be a master coordinator of a genetic growth network in mice. We observe PLAGL1 binding to the H19/IGF2 shared enhancers in placentae, with significant correlations between PLAGL1 levels with H19 and IGF2 expression levels. In addition, PLAGL1 binding and expression also correlate with expression levels of metabolic regulator genes SLC2A4, TCF4 and PPARγ1. Our results strongly suggest that fetal growth can be influenced by altered expression of the PLAGL1 gene network in human placenta.
authors.affiliation: Servicio de Neonatología, Hospital Sant Joan de Déu, Fundació Sant Joan de Déu, Barcelona 08950, Spain, iiglesias@hsjdbcn.org dmonk@idibell.cat.
authors.forename: Isabel
authors.initials: I
authors.lastname: Iglesias-Platas
authors.affiliation: Imprinting and Cancer Group.
authors.forename: Alex
authors.initials: A
authors.lastname: Martin-Trujillo
authors.affiliation: Cancer Epigenetics Group, Cancer Epigenetic and Biology Program, Institut D'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona 08907, Spain.
authors.forename: Paolo
authors.initials: P
authors.lastname: Petazzi
authors.affiliation: Servicio de Neonatología, Hospital Sant Joan de Déu, Fundació Sant Joan de Déu, Barcelona 08950, Spain, Imprinting and Cancer Group.
authors.forename: Amy
authors.initials: A
authors.lastname: Guillaumet-Adkins
authors.affiliation: Cancer Epigenetics Group, Cancer Epigenetic and Biology Program, Institut D'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona 08907, Spain, Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona 08097, Spain and Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia 08010, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Imprinting and Cancer Group, iiglesias@hsjdbcn.org dmonk@idibell.cat.
authors.forename: David
authors.initials: D
authors.lastname: Monk
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism*; D053263:Gene Regulatory Networks; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012737:Sex Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C106464:PLAGL1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins