Intrauterine growth restriction inhibits expression of eukaryotic elongation factor 2 kinase, a regulator of protein translation.
Nutrient deprivation suppresses protein synthesis by blocking peptide elongation. Transcriptional upregulation and activation of eukaryotic elongation factor 2 kinase (eEF2K) blocks peptide elongation by phosphorylating eukaryotic elongation factor 2. Previous studies examining placentas from intrauterine growth restricted (IUGR) newborn infants show decreased eEF2K expression and activity despite chronic nutrient deprivation. However, the effect of IUGR on hepatic eEF2K expression in the fetus is unknown. We, therefore, examined the transcriptional regulation of hepatic eEF2K gene expression in a Sprague-Dawley rat model of IUGR. We found decreased hepatic eEF2K mRNA and protein levels in IUGR offspring at birth compared with control, consistent with previous placental observations. Furthermore, the CpG island within the eEF2K promoter demonstrated increased methylation at a critical USF 1/2 transcription factor binding site. In vitro methylation of this binding site caused near complete loss of eEF2K promoter activity, designating this promoter as methylation sensitive. The eEF2K promotor in IUGR offspring also lost the protective histone covalent modifications associated with unmethylated CGIs. In addition, the +1 nucleosome was displaced 3' and RNA polymerase loading was reduced at the IUGR eEF2K promoter. Our findings provide evidence to explain why IUGR-induced chronic nutrient deprivation does not result in the upregulation of eEF2K gene transcription.
Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; and robert.mcknight@hsc.utah.edu.
Robert A
0000-0002-1435-6492
RA
McKnight
Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; and.
Christian C
CC
Yost
Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; and.
Erin K
0000-0001-6085-6976
EK
Zinkhan
Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Qi
Q
Fu
Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; and.
Christopher W
CW
Callaway
Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; and.
Camille M
CM
Fung
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D054736:Elongation Factor 2 Kinase / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D005333:Fetus / Q000378:metabolism; D008297:Male; D009707:Nucleosomes / Q000235:genetics; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D009707:Nucleosomes; D012333:RNA, Messenger; C517691:Eef2k protein, rat; D054736:Elongation Factor 2 Kinase
DNA methylation; IUGR; eEF2K; epigenetic; nucleosome