Intrauterine growth restriction disrupts developmental epigenetics around distal growth hormone response elements on the rat hepatic IGF-1 gene. FASEB J 2015 Apr;29(4):1176-84
Date
12/04/2014Pubmed ID
25466885DOI
10.1096/fj.14-258442Scopus ID
2-s2.0-84931304700 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
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.
Author List
Fu Q, McKnight RA, Callaway CW, Yu X, Lane RH, Majnik AVMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Binding Sites
CpG Islands
DNA Methylation
Epigenesis, Genetic
Female
Fetal Growth Retardation
Gene Expression Regulation, Developmental
Histones
Insulin-Like Growth Factor I
Liver
Male
Pregnancy
Rats
Rats, Sprague-Dawley
Response Elements
STAT5 Transcription Factor
