Uteroplacental insufficiency alters DNA methylation, one-carbon metabolism, and histone acetylation in IUGR rats

Abstract

. Uteroplacental insufficiency alters DNA methylation, one-carbon metabolism, and histone acetylation in IUGR rats. Physiol Genomics 18: 43-50, 2004. First published April 13, 2004 10.1152/physiolgenomics.00042.2004.-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-␤-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.intrauterine growth retardation; one-carbon metabolism; epigenetics; Barker's fetal origins of adult disease hypothesis BARKER'S "fetal origins of adult disease hypothesis" proposes that fetal adaptation to a deprived intrauterine milieu leads to permanent changes in cellular biology and systemic physiology. Intrauterine growth retardation (IUGR) predisposes affected newborns toward long-term morbidity from type 2 diabetes, as well as other components of the metabolic syndrome (2). Uteroplacental insufficiency, a morbidity associated with many common complications of pregnancy such as preeclampsia, induces low ponderal index or asymmetrical IUGR. In the rat, uteroplacental insufficiency induced through bilateral uterine artery ligation of the pregnant dam also results in asymmetrical IUGR and, similar to the human, causes fetal hypoinsulinemia, hypoglycemia, acidosis, and hypoxia (5,14,16,39,40). Juvenile IUGR rats demons...

Sexual dimorphism in environmental epigenetic programming

“…Histone modifications are also induced at the GR promoter [36]. Uteroplacental insufficiency alters DNA methylation, with genome-wide DNA hypomethylation and large amounts of acetylated histone H3 after birth in the liver [45]. In the kidney, decreases in CpG methylation of a specific site within the promoter of the p53 gene and relative hypomethylation of the DNMT1 gene are observed [46].…”

Effect of intrauterine growth retardation on liver and long-term metabolic risk

“…7 There is evidence showing that early exposure to suboptimal environment induces epigenetic changes predisposing to type 2 diabetes (Table 1). [22][23][24][25] In rats, the exposure to uteroplacental insufficiency induces hepatic DNA hypomethylation and histone hyperacetylation of histone H3 on lysine 9 (H3K9), lysine 14 (H3K14) and lysine 18 (H3K18) at birth 26 These changes persist up to day 21 of postnatal life, suggesting a permanent effect on hepatic gene expression. The hyperacetylation on histone H3 in the liver of IUGR rats occurs in association with decreased nuclear protein levels of histone deacetylase 1 (HDAC1) and HDAC activity.…”

Pre-birth origins of allergy and asthma

“…In rodent models of PR, fetal 1-carbon donor abundance is decreased, 1-carbon pathway enzyme expression is altered and this is associated with hypomethylation of DNA and increased histone acetylation in multiple tissues (MacLennan et al 2004, Ke et al 2006, Park et al 2008. Consistent with the hypothesis that reduced placental methyl donor transport to the fetus protects against allergy in the PR sheep, when we supplemented PR ewes with methyl donors and cofactors in the last month of their five month gestation, the protective effects of PR against cutaneous delayed-type hypersensitivity after allergen sensitisation were partially lost (Wooldridge et al, unpublished).…”