Uteroplacental insufficiency alters DNA methylation, one-carbon metabolism, and histone acetylation in IUGR rats. Physiol Genomics 2004 Jun 17;18(1):43-50
Date
04/16/2004Pubmed ID
15084713DOI
10.1152/physiolgenomics.00042.2004Scopus ID
2-s2.0-4844229628 (requires institutional sign-in at Scopus site) 183 CitationsAbstract
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.
Author List
MacLennan NK, James SJ, Melnyk S, Piroozi A, Jernigan S, Hsu JL, Janke SM, Pham TD, Lane RHMESH terms used to index this publication - Major topics in bold
AcetylationAnimals
Carbon
Chromatin
Cystathionine beta-Synthase
DNA Methylation
Disease Models, Animal
Disease Susceptibility
Enzyme Induction
Female
Fetal Growth Retardation
Gene Expression Regulation, Developmental
Gestational Age
Histones
Liver
Methionine
Methionine Adenosyltransferase
Placental Circulation
Placental Insufficiency
Pregnancy
Protein Processing, Post-Translational
Rats
S-Adenosylhomocysteine