Intrauterine growth restriction alters the epigenetic profile and decreases RNA of Stearoyl CoA Desaturase in newborn rat lung

Intrauterine growth restriction (IUGR) is associated with impaired lung development and function. Lung function is impaired in IUGR rats, in part, by altered surfactant composition. The lipid profile in lungs determines surfactant lipid composition. Our IUGR rats have decreased lung palmitoleic acid (16:1). Stearoyl CoA Desaturase (SCD), the rate-limiting enzyme in synthesis of palmitoleic acid, is a target of transcription factor peroxisome proliferator activated receptor gamma (PPARγ) and is susceptible to transcriptional regulation through epigenetic modifications. There are a number of genes in the lung that show altered mRNA levels in association with decreased PPARγ levels and epigenetic modifications in the presence of IUGR. The effect of IUGR on the epigenetic profile of SCD as well as SCD mRNA and protein levels in the newborn rat lung is unknown. We hypothesize that IUGR will be associated with reduced SCD mRNA and protein levels consistent with the previously observed decrease in PPARγ levels in the lungs of d0 rat pups. We further hypothesize that there will be gender-specific changes in the epigenetic profile along the length of the SCD gene. This hypothesis was tested using a uteroplacental insufficiency (UPI) model of IUGR in rats. Whole lung tissue was harvested at birth (d0) and used to assess SCD mRNA and protein levels by RT-PCR and western blot analysis. Epigenetic modifications (H3K14Ac and H3K36Me3) were assessed along the SCD gene using chromatin immunoprecipitation (ChIP). Results showed that, in control lungs females have 153% higher SCD mRNA than males (p=0.005). A consistent decrease in SCD mRNA levels was found in both male and female IUGR rats at birth relative to controls (p=0.009, p=0.0023). H3K14Ac was increased at SCD exon 4 in IUGR females to 210% of the level detected in gender-matched controls (p=0.037). H3K3Me3 was decreased at SCD exon 4 in IUGR males by 43% (p=0.044) and at SCD 3'UTR in IUGR females by 65% relative to gender-matched controls (p=0.036). There was no change in SCD protein levels in IUGR rats at birth. In conclusion IUGR is associated with decreased SCD mRNA levels and gender-specific changes to the epigenetic profile along the SCD gene.