ESPE Yearbook of Paediatric Endocrinology

Nat Commun. 2018; 9(1): 2555. doi: 10.1038/s41467-018-04992-1.

https://www.ncbi.nlm.nih.gov/pubmed/?term=29967448

Sex differences in human disease have been extensively described for some of the most prevalent health conditions affecting societies today, from hypertension to diabetes, arthritis, and cancers. However, the mechanism for different disease vulnerability between sexes is not known.

Here the authors investigate whether female prenatal resilience is driven by sex differences in placental transcriptional control by the X-linked gene, O-linked N-acetylglucosamine transferase (OGT) and its regulation of the histone repressive mark, H3K27me3. The study included both human placental tissue and a mouse model of prenatal stress to elucidate the underlying mechanisms. The study provides evidence that one mechanism whereby OGT contributes to variation in vulnerability to prenatal stress between sexes is by establishing sex-specific trophoblast gene expression patterns and via regulation of the canonically repressive epigenetic modification, H3K27me3. Moreover, the authors show that high levels of H3K27me3 in the female placenta create resilience to the altered hypothalamic programming associated with prenatal stress exposure. The results highlight the importance of the placenta as a mediator between the maternal milieu and fetal development. Understanding these mechanisms may confer knowledge on the programming of the brain and on how male-biased neurodevelopmental diseases develop.