title: Intrauterine growth restriction disrupts developmental epigenetics around distal growth hormone response elements on the rat hepatic IGF-1 gene.
abstract: Intrauterine growth restriction (IUGR) decreases serum IGF-1 levels. Postnatal IGF-1 expression is transcriptionally regulated by growth hormone (GH) through growth hormone response elements (GHREs). We hypothesized that IUGR disrupts the normal developmental maturation of hepatic IGF-1 intron 2 growth hormone response element (IN2GHRE) histone methylation of key lysines and DNA methylation. We also evaluated a 5' distal weak enhancer (IGF-1 5'-upstream region growth hormone response element; 5URGHRE) as a GHRE specificity control. IUGR was induced through a well-characterized model of bilateral uterine artery ligation of the pregnant rat. Offspring livers were tested at d 0 and 21. Chromatin immunoprecipitation and bisulfite sequencing quantified epigenetic characteristics. We found that distinct age-related developmental patterns of histone and DNA methylation characterize each GHRE. Development increased H3K4 trimethylation (me3) in both GHREs. However, H3K9me3 decreased with age at IN2GHRE and increased with age at 5URGHRE. IUGR altered the developmental pattern of H3K4me3 and K9me3 around the GHREs in a sex-specific manner at d 21. Developmental and IUGR-induced DNA methylation occurred in a GHRE-, CpG site-, and sex-specific manner. We conclude that IUGR disrupts developmental epigenetics around distal GHREs on the rat hepatic IGF-1 gene.
authors.affiliation: *Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; and Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Fu
authors.affiliation: *Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; and Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: McKnight
authors.affiliation: *Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; and Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Callaway
authors.affiliation: *Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; and Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Yu
authors.affiliation: *Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; and Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lane
authors.affiliation: *Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; and Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA amajnik@mcw.edu.
authors.forename: Amber V
authors.initials: AV
authors.lastname: Majnik
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D006657:Histones; D050799:STAT5 Transcription Factor; C494097:Stat5b protein, rat; D007334:Insulin-Like Growth Factor I
keywords: DNA; enhancer; histone; methylation; prenatal