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1 Department of Pediatrics, Division of Neonatology and Developmental Biology, Mattel Children's Hospital @ UCLA, David Geffen School of Medicine @ UCLA, Los Angeles, CA, USA
2 Department of Pediatrics, University of Arkansas for Medical Sciences, Little, AR, USA
3 Division of Neonatology, University of Utah, Salt Lake City, UT, USA
4 Department of Pediatrics, Division of Neonatology and Developmental Biology, Mattel Children's Hospital @ UCLA, David Geffen School of Medicine @ UCLA, Los Angeles, CA, USA; Division of Neonatology, University of Utah, Salt Lake City, UT, USA
* To whom correspondence should be addressed. E-mail: robert.lane{at}hsc.utah.edu.
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 methylase assay and two dimensional thin layer chromatography demonstrated genomic 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 
-synthase. Western blotting further demonstrated that increased quantities of acetylated histone 3 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.
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