Adverse Maternal Environment Increases Fetal Liver Hydroxymethylation and Alters the Transcriptome

Authors: FU, QI - Medical College Of Wisconsin; Li, Wenli; MAJNIK, AMBER - Medical College Of Wisconsin; KE, XINAGRAO - Medical College Of Wisconsin; LANE, ROBERT - Medical College Of Wisconsin

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 2/16/2018
Publication Date: N/A
Citation: N/A

Interpretive Summary:

Technical Abstract: Suboptimal maternal nutrition during fetal liver development can alter the offspring’s ability to metabolize excess fats and increases obesity in offspring. We developed a model of adverse maternal environment (AME) which overlays maternal prenatal stress with chronic exposure to a western diet. Offspring exposed to this environment gain more weight when exposed to a post weaning western diet compared to offspring exposed to a control maternal environment. Environmentally driven changes in fetal metabolism are thought to occur through shifts in epigenetic patterns, particularly waves of DNA demethylation and remethylation. Demethylation takes place through hydroxymethylation, a stable DNA modification which positively correlates with gene expression and actively regulates transcription. We therefore sought to understand how an AME alters long term metabolism by measuring epigenetic and transcriptional changes in the fetal liver. We hypothesize that an AME will alter fetal liver hydroxymethylation and modify the transcription of metabolic genes. Female mice were exposed to either a control or western diet 5 weeks prior to pregnancy and throughout lactation. We added non-invasive variable stressors during last third of pregnancy to dams on the western diet only creating an Adverse Maternal Environment (AME). Livers of offspring were harvested just prior to natural delivery on embryonic day 19.5 and total DNA and RNA was isolated. Hydroxymethylation was quantitated with a colorimetric ELISA kit. RNA-Seq was performed to generate the transcriptome. The AME male and female offspring transcriptome was compared to gender matched controls. Real Time RT-PCR was used to confirm RNA-Seq findings.AME significantly increased total hydroxymethylation 1.5 fold in males and 3.4 fold in female samples (p<0.05). RNA-Seq identified 31 significantly differentially-expressed genes in the AME males compared to controls and 10 significantly differentially expressed genes in AME females. Expression of some differentially expressed metabolic genes including; GLUT1, SOCS2, Abcg8, and Setd7 was confirmed by real time AME increased fetal liver hydroxymethylation and altered the transcriptional output. We speculate that maternal environment alters the regulation of hydroxymethylation that in turn shifts the transcriptional output which underscores the metabolic framework for increased weight gain when offspring are exposed to a post weaning western diet.