Intrauterine growth restriction disrupts developmental epigenetics around distal growth hormone response elements on the rat hepatic IGF‐1 gene

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 gro...

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Published in:The FASEB journal 2015-04, Vol.29 (4), p.1176-1184
Main Authors: Fu, Qi, McKnight, Robert A., Callaway, Christopher W., Yu, Xing, Lane, Robert H., Majnik, Amber V.
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Binding Sites - genetics
CpG Islands
DNA Methylation
enhancer
Epigenesis, Genetic
Female
Fetal Growth Retardation - genetics
Fetal Growth Retardation - metabolism
Gene Expression Regulation, Developmental
histone · DNA
Histones - metabolism
Insulin-Like Growth Factor I - genetics
Liver - metabolism
Male
methylation
Pregnancy
prenatal
Rats
Rats, Sprague-Dawley
Response Elements
STAT5 Transcription Factor - metabolism
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Summary: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‐15‘‐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.—Fu, Q., McKnight, R. A., Callaway, C. W., Yu, X., Lane, R. H., Majnik, A. V. Intrauterine growth restriction disrupts developmental epigenetics around distal growth hormone response elements on the rat hepatic IGF‐1 gene. FASEB J. 29, 1176‐1184 (2015). www.fasebj.org
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.14-258442