title: Intrauterine growth restriction affects hippocampal dual specificity phosphatase 5 gene expression and epigenetic characteristics.
abstract: Intrauterine growth retardation (IUGR) predisposes humans toward hippocampal morbidities, such as impaired learning and memory. Hippocampal dual specificity phosphatase 5 (DUSP5) may be involved in these morbidities because DUSP5 regulates extracellular signal-regulated kinase phosphorylation (Erk). In the rat, IUGR causes postnatal changes in hippocampal gene expression and epigenetic characteristics. However, the impact of IUGR upon hippocampal DUSP5 expression and epigenetic characteristics is not known. We therefore hypothesized that IUGR affects hippocampal 1) DUSP5 expression, DNA CpG methylation, and histone code, and 2) erk1/2 phosphorylation in a well-characterized rat model of IUGR. We found that IUGR significantly decreased DUSP5 expression in the day of life (DOL) 0 and 21 male rat, while decreasing only DUSP5 protein levels in the DOL21 female rat. Fluorescent in situ hybridization and immunohistochemistry analyses localized the changes in DUSP5 mRNA and protein, many of which occurred in the dentate gyrus. IUGR also caused sex-specific differences in DNA CpG methylation and histone code in two sites of the hippocampal DUSP5 gene, a 5'-flanking specificity protein-1 (SP1) site and exon 2. Finally, when IUGR decreased DUSP5 protein levels, Erk phosphorylation increased. We conclude that IUGR affects hippocampal DUSP5 expression and epigenetic characteristics in a sex-specific manner.
authors.affiliation: University of Utah School of Medicine, Department of Pediatrics, Division of Neonatology, Salt Lake City, Utah 84132-2202, USA.
authors.forename: Xingrao
authors.initials: X
authors.lastname: Ke
authors.forename: Robert A
authors.initials: RA
authors.lastname: McKnight
authors.forename: Diana
authors.initials: D
authors.lastname: Caprau
authors.forename: Shannon
authors.initials: S
authors.lastname: O'Grady
authors.forename: Qi
authors.initials: Q
authors.lastname: Fu
authors.forename: Xing
authors.initials: X
authors.lastname: Yu
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Callaway
authors.forename: Kurt H
authors.initials: KH
authors.lastname: Albertine
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lane
mesh_terms: D000818:Animals; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D054637:Dual-Specificity Phosphatases / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000201:enzymology* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D042421:Histone Code; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D054637:Dual-Specificity Phosphatases; C514214:Dusp5 protein, rat