Carla Caniçais1,2, Sara Vasconcelos1,2, Carla Ramalho2,3, C Joana Marques4,5, Sofia Dória6,7. 1. Department of Genetics, Faculty of Medicine, University of Porto, 4200-319, Porto, Portugal. 2. i3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal. 3. Department of Obstetrics and Gynecology, Faculty of Medicine, Hospital São João, Porto, Portugal. 4. Department of Genetics, Faculty of Medicine, University of Porto, 4200-319, Porto, Portugal. cmarques@med.up.pt. 5. i3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal. cmarques@med.up.pt. 6. Department of Genetics, Faculty of Medicine, University of Porto, 4200-319, Porto, Portugal. sdoria@med.up.pt. 7. i3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal. sdoria@med.up.pt.
Abstract
PURPOSE: Intrauterine growth restriction (IUGR) is a fetal growth complication that can be caused by ineffective nutrient transfer from the mother to the fetus via the placenta. Abnormal placental development and function have been correlated with abnormal expression of imprinted genes, which are regulated by epigenetic modifications at imprinting control regions (ICRs). In this study, we analyzed the expression of imprinted genes known to be involved in fetal growth and epigenetic regulators involved in DNA methylation, as well as DNA methylation at the KvDMR1 imprinting control region and global levels of DNA hydroxymethylation, in IUGR cases. METHODS: Expression levels of imprinted genes and epigenetic regulators were analyzed in term placental samples from 21 IUGR cases and 9 non-IUGR (control) samples, by RT-qPCR. Additionally, KvDMR1 methylation was analyzed by bisulfite sequencing and combined bisulfite restriction analysis (COBRA) techniques. Moreover, global DNA methylation and hydroxymethylation levels were also measured. RESULTS: We observed increased expression of PHLDA2, CDKN1C, and PEG10 imprinted genes and of DNMT1, DNMT3A, DNMT3B, and TET3 epigenetic regulators in IUGR placentas. No differences in methylation levels at the KvDMR1 were observed between the IUGR and control groups; similarly, no differences in global DNA methylation and hydromethylation were detected. CONCLUSION: Our study shows that deregulation of epigenetic mechanisms, namely increased expression of imprinted genes and epigenetic regulators, might be associated with IUGR etiology. Therefore, this study adds knowledge to the molecular mechanisms underlying IUGR, which may contribute to novel prediction tools and future therapeutic options for the management of IUGR pregnancies.
PURPOSE: Intrauterine growth restriction (IUGR) is a fetal growth complication that can be caused by ineffective nutrient transfer from the mother to the fetus via the placenta. Abnormal placental development and function have been correlated with abnormal expression of imprinted genes, which are regulated by epigenetic modifications at imprinting control regions (ICRs). In this study, we analyzed the expression of imprinted genes known to be involved in fetal growth and epigenetic regulators involved in DNA methylation, as well as DNA methylation at the KvDMR1 imprinting control region and global levels of DNA hydroxymethylation, in IUGR cases. METHODS: Expression levels of imprinted genes and epigenetic regulators were analyzed in term placental samples from 21 IUGR cases and 9 non-IUGR (control) samples, by RT-qPCR. Additionally, KvDMR1 methylation was analyzed by bisulfite sequencing and combined bisulfite restriction analysis (COBRA) techniques. Moreover, global DNA methylation and hydroxymethylation levels were also measured. RESULTS: We observed increased expression of PHLDA2, CDKN1C, and PEG10 imprinted genes and of DNMT1, DNMT3A, DNMT3B, and TET3 epigenetic regulators in IUGR placentas. No differences in methylation levels at the KvDMR1 were observed between the IUGR and control groups; similarly, no differences in global DNA methylation and hydromethylation were detected. CONCLUSION: Our study shows that deregulation of epigenetic mechanisms, namely increased expression of imprinted genes and epigenetic regulators, might be associated with IUGR etiology. Therefore, this study adds knowledge to the molecular mechanisms underlying IUGR, which may contribute to novel prediction tools and future therapeutic options for the management of IUGR pregnancies.
Entities:
Keywords:
DNA hydroxymethylation; DNA methylation; Genomic imprinting; Intrauterine growth restriction; Placenta
Authors: F F Bressan; T H C De Bem; F Perecin; F L Lopes; C E Ambrosio; F V Meirelles; M A Miglino Journal: Placenta Date: 2009-08-12 Impact factor: 3.481
Authors: David J Harrison; Hugo D J Creeth; Hannah R Tyson; Raquel Boque-Sastre; Susan Hunter; Dominic M Dwyer; Anthony R Isles; Rosalind M John Journal: Hum Mol Genet Date: 2021-09-15 Impact factor: 6.150