The omniscient placenta: Metabolic and epigenetic regulation of fetal programming

Abstract

Fetal development could be considered a sensitive period wherein exogenous insults and changes to the maternal milieu can have long-term impacts on developmental programming. The placenta provides the fetus with protection and necessary nutrients for growth, and responds to maternal cues and changes in nutrient signaling through multiple epigenetic mechanisms. The X-linked enzyme O-linked-N-acetylglucosamine transferase (OGT) acts as a nutrient sensor that modifies numerous proteins to alter various cellular signals, including major epigenetic processes. This review describes epigenetic alterations in the placenta in response to insults during pregnancy, the potential links of OGT as a nutrient sensor to placental epigenetics, and the implications of placental epigenetics in long-term neurodevelopmental programming. We describe the role of placental OGT in the sex-specific programming of hypothalamic-pituitary-adrenal (HPA) axis programming deficits by early prenatal stress as an example of how placental signaling can have long-term effects on neurodevelopment.

Keywords: Epigenetics; Fetal development; Neurodevelopment; Nutrition; OGT; Placenta; Stress.

Figure 1

Nutritional requirments for brain development. During late gestation, specific nutritional inputs (center) to the brain are necessary for specific neurodevelopmental processes (left). These nutrients come from either maternal circulation and the placenta combined (broken arrows) or maternal circulation alone (solid arrows). Their mechanism of transport across the placenta also differs (indicated by arrow color).

Figure 2

Sex differences in epigenetic regulation of placental gene expression. A. Sex chromosome complement leads to male biased expression of the Y-linked histone demethylases Kdm5d and Uty, and female biased expression of the histone demethylase Kdm5c. B. DNA in the female placenta is more heavily methylated than in the male placenta. C. To date, there have not been reports of sex difference in miRNA expression in the placenta. D. Expression of the X-linked nutrient sensing enzyme O-linked N-acetlyglucosamine (O-GlcNAc) transferase (OGT) is higher in the female placenta, leading to numerous sex differences in chromatin regulatory processes.