Uteroplacental insufficiency induces site-specific changes in histone H3 covalent modifications and affects DNA-histone H3 positioning in day 0 IUGR rat liver

Abstract

Uteroplacental insufficiency and subsequent intrauterine growth retardation (IUGR) increase the risk of adult onset insulin resistance and dyslipidemia in humans and rats. IUGR rats are further characterized by postnatal alterations in hepatic PPAR-gamma coactivator (PGC-1) and carnitine-palmitoyl-transferase I (CPTI) expression, as well as overall hyperacetylation of histone H3. However, it is unknown whether the histone H3 hyperacetylation is site specific or relates to the changes in gene expression previously described in IUGR rats. We therefore hypothesized that uteroplacental insufficiency causes site-specific modifications in hepatic H3 acetylation and affects the association of acetylated histone H3 with PGC-1 and CPTI promoter sequences. Uteroplacental insufficiency was used to produce asymmetrical IUGR rats. IUGR significantly increased acetylation of H3 lysine-9 (H3/K9), lysine-14 (H3/K14), and lysine-18 (H3/K18) at day 0 of life, and these changes occurred in association with decreased nuclear protein levels of histone deacetylase 1 (HDAC1) and HDAC activity. Chromatin immunoprecipitation using acetyl-H3/K9 antibody and day 0 chromatin revealed that uteroplacental insufficiency affected the association between acetylated H3/K9 and the promoters of PGC-1 and CPTI, respectively, in IUGR liver. At day 21 of life, the neonatal pattern of H3 hyperacetylation persisted only in the IUGR males. We conclude that uteroplacental insufficiency increases H3 acetylation in a site-specific manner in IUGR liver and that these changes persist in male IUGR animals. The altered association of the PGC-1 and CPTI promoters with acetylated H3/K9 correlates with previous reports of IUGR altering the expression of these genes. We speculate that in utero alterations of chromatin structure contribute to fetal programming.

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.…”

“…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. 22 These sitespecific changes in histone H3 acetylation alter the histone association with the promoter regions of PPAR-gamma coactivator (PGC-1) and carnitine-palmitoyl transferase I (CPTI), two genes that are persistently altered in the rat with intrauterine growth retardation. It is noteworthy that PGC-1 expression is increased, whereas CPTI expression is reduced in IUGR rats predisposed to develop diabetes.…”

“…34 Interestingly, the subjects exposed to famine periconceptionally showed, 60 years later, decreased methylation of IGF-II, whereas no change in the degree of IGF-II methylation was observed in those exposed to famine late in gestation. 35 The reduced methylation of IGF-II may represent the 22 Liver CPT-I Rate-limiting transporter in mitochondrial fatty acid b-oxidation H3K9 hyperacetylation affecting association with gene promoter IUGR rats 23 Pancreatic islets PDX-1 Transcription factor critical for b-cell function and development H3 and H4 deacetylation, H3K4 demethylation, H3K9 methylation IUGR rats 24 Skeletal muscle GLUT4 Glucose transporter H3K14 de-acetylation; H3K9 methylation IUGR rats 25 Pancreatic islets CGH-1 Role in endothelial dysfunction and b-cell development CpG hypermethylation in intergenic sequences IUGR rats 25 Pancreatic islets FGFR-1 Fibroblast growth factor receptor CpG hypomethylation in intergenic sequences IUGR rats 25 Pancreatic islets PCSK-5 Role in peptide processing and maturation CpG hypermethylation in transcription start site Humans 35 Blood IGF-II Fetal growth CpG hypomethylation…”

Epigenetics and maternal nutrition: nature v. nurture

“…A number of studies suggest that uteroplacental insufficiency, a common cause of IUGR, induces epigenetic modifications in offspring (97)(98)(99)(100) . Epigenetic modifications affecting processes important to glucose regulation and insulin secretion, characteristics essential to the pathophysiology of T2D have been described in the IUGR liver, pancreatic b-cells and muscle (97)(98)(99)(100) .…”

“…Epigenetic modifications affecting processes important to glucose regulation and insulin secretion, characteristics essential to the pathophysiology of T2D have been described in the IUGR liver, pancreatic b-cells and muscle (97)(98)(99)(100) .…”