title: Uteroplacental insufficiency alters DNA methylation, one-carbon metabolism, and histone acetylation in IUGR rats.
abstract: Uteroplacental insufficiency leads to intrauterine growth retardation (IUGR) and increases the risk of insulin resistance and hypertriglyceridemia in both humans and rats. Postnatal changes in hepatic gene expression characterize the postnatal IUGR rat, despite the transient nature of the initial in utero insult. Phenomena such as DNA methylation and histone acetylation can induce a relatively static reprogramming of gene transcription by altering chromatin infrastructure. We therefore hypothesized that uteroplacental insufficiency persistently affects DNA methylation and histone acetylation in the IUGR rat liver. IUGR rat pups were created by inducing uteroplacental insufficiency through bilateral uterine artery ligation of the pregnant dam on day 19 of gestation. The SssI methyltransferase assay and two-dimensional thin-layer chromatography demonstrated genome-wide DNA hypomethylation in postnatal IUGR liver. To investigate a possible mechanism for this hypomethylation, levels of hepatic metabolites and enzyme mRNAs involved in one-carbon metabolism were measured using HPLC with coulometric electrochemical detection and real-time RT-PCR, respectively. Uteroplacental insufficiency increased IUGR levels of S-adenosylhomocysteine, homocysteine, and methionine in association with decreased mRNA levels of methionine adenosyltransferase and cystathionine-beta-synthase. Western blotting further demonstrated that increased quantities of acetylated histone H3 also characterized the IUGR liver. Increased hepatic levels of S-adenosylhomocysteine can promote DNA hypomethylation, which is often associated with histone hyperacetylation. We speculate that the altered intrauterine milieu associated with uteroplacental insufficiency affects hepatic one-carbon metabolism and subsequent DNA methylation, which thereby alters chromatin dynamics and leads to persistent changes in hepatic gene expression.
authors.affiliation: David Geffen School of Medicine, UCLA, Department of Pediatrics, Division of Neonatology and Developmental Biology, Mattel Children's Hospital, UCLA, Los Angeles, California, 90095-1752, USA.
authors.forename: Nicole K
authors.initials: NK
authors.lastname: MacLennan
authors.forename: S Jill
authors.initials: SJ
authors.lastname: James
authors.forename: Stephan
authors.initials: S
authors.lastname: Melnyk
authors.forename: Ali
authors.initials: A
authors.lastname: Piroozi
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jernigan
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hsu
authors.forename: Sara M
authors.initials: SM
authors.lastname: Janke
authors.forename: Tho D
authors.initials: TD
authors.lastname: Pham
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lane
mesh_terms: D000107:Acetylation; D000818:Animals; D002244:Carbon / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics; D003541:Cystathionine beta-Synthase / Q000096:biosynthesis / Q000235:genetics; D019175:DNA Methylation; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004790:Enzyme Induction; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005865:Gestational Age; D006657:Histones / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D008716:Methionine Adenosyltransferase / Q000096:biosynthesis / Q000235:genetics; D021041:Placental Circulation; D010927:Placental Insufficiency / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D051381:Rats; D012435:S-Adenosylhomocysteine / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D002244:Carbon; D012435:S-Adenosylhomocysteine; D008715:Methionine; D008716:Methionine Adenosyltransferase; D003541:Cystathionine beta-Synthase