While self-help books may suggest that women are from Mars and men are from Venus, exciting new findings demonstrate that the study of epigenetic modifications offers an astronomically better explanation for the differences between males and females. Inspired by research indicating that males suffer from greater vulnerability to prenatal stress and certain psychiatric conditions, the lab of Tracy Bale at the University of Maryland turned to the interface between the developing fetus and its mother: the placenta. As the placenta derives from the fetus, this multifunctional organ offers the perfect chance to examine how sex-based alterations arise in early-life.
The group previously examined the placental O-linked N-acetylglucosamine transferase (OGT) enzyme, discovering that sex-based differences in OGT play a mechanistic role in the effects of prenatal stress on neurodevelopment. Inspired by another study demonstrating that OGT can shape H3K27me3 profiles by stabilizing EZH2, a part of the polycomb repressive complex 2 (PRC2), the team sought to examine if higher levels of OGT expression create a transcriptional profile of resilience to prenatal stress in females. Their experiments made use of females with an X-chromosome missing one OGT allele, which thus displayed male OGT expression levels.
Here’s what they uncovered in their mouse model:
- By using RNA-seq and RiboTag technology to examine only embryonic placental (trophoblast) cells, the group discovered that females hemizygous for a trophoblast cell-restricted OGT deletion exhibit a masculinized gene expression profile
- The masculinized gene expression profile is also present in the embryonic hypothalamus, a brain region critical to the stress response, which demonstrates that the altered transcriptomic profile goes beyond trophoblast cells with altered OGT dosage and represents a trans-placental signal
- Western blots and ChIP-seq for H3K27me3 demonstrated that OGT dosage controls placental H327me3 levels both globally and at transcription start sites, respectively
- Deletion of Ezh2 in the placenta creates a vulnerability to prenatal stress in females that mirrors previous studies in males
These findings also suggest that OGT probably acts through multiple epigenetic mechanisms, as there was little overlap between the gene expression profiles of hypothalami from Ezh2 knockout females with OGT hemizygous females. Senior author Tracy Bale concludes, “This pathway could help explain why we see this profound neurodevelopmental difference in humans. OGT and H3K27me3 in the placenta are crucial to a lot of protein-encoding that occurs during pregnancy, and so this process has a lot of downstream effects. The OGT gene is on the X chromosome, and seems to provide a level of protection for the female fetus to perturbations in the maternal environment.”
Taken together, this research uncovers the epigenetic mechanisms that mediate sex-based differences in trans-placental signals, which shape neurodevelopmental vulnerability and resilience.