Epigenetics: intrauterine growth retardation (IUGR) modifies the histone code along the rat hepatic IGF-1 gene

FASEB J. 2009 Aug;23(8):2438-49. doi: 10.1096/fj.08-124768. Epub 2009 Apr 13.


Intrauterine growth restriction (IUGR) decreases serum insulin growth factor-1 (IGF-1) levels. IGF-1 is an epigenetically regulated gene that has two promoters, alternative exon 5 splicing, and multiple termination sites. The regulation of gene expression involves the whole gene, as evidenced by the aforementioned IGF-1 paradigm. We hypothesized that IUGR in the rat would affect hepatic IGF-1 expression and alter the epigenetic characteristics of the IGF-1 gene along its length. IUGR was induced through a bilateral uterine artery ligation of the pregnant rat, a well-characterized model of IUGR. Pups from anesthesia and sham-operated dams were used as controls. Real-time RT-PCR and ELISA was used to measure expression at day of life (DOL) 0 and 21. Bisulfite sequencing and chromatin immunoprecipitation (ChIP) quantified IGF-1 epigenetic characteristics. A nontranscribed intergenic control was used for ChIP studies. IUGR decreased hepatic and serum IGF-1. Concurrently, IUGR modified epigenetic characteristics, particularly the histone code, along the length of the hepatic IGF-1 gene. Many changes persisted postnatally, and the postnatal effect of IUGR on the histone code was gender-specific. We conclude that IUGR modifies epigenetic characteristics of the rat hepatic IGF-1 gene along the length of the whole gene.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing
  • Animals
  • Animals, Newborn
  • Base Sequence
  • DNA Methylation
  • DNA Primers / genetics
  • Epigenesis, Genetic*
  • Female
  • Fetal Growth Retardation / genetics*
  • Fetal Growth Retardation / metabolism
  • Gene Expression Regulation, Developmental
  • Histones / genetics*
  • Insulin-Like Growth Factor I / genetics*
  • Insulin-Like Growth Factor I / metabolism
  • Liver / metabolism*
  • Male
  • Pregnancy
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley


  • DNA Primers
  • Histones
  • RNA, Messenger
  • Insulin-Like Growth Factor I