Placental H3K27me3 establishes female resilience to prenatal insults

Bridget M Nugent,Carly M O’Donnell,Tracy L Bale,C Neill Epperson

doi:10.1038/s41467-018-04992-1

Bridget M Nugent, Carly M O’Donnell + Show 2 more

Open Access

https://doi.org/10.1038/s41467-018-04992-1

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Abstract

Although sex biases in disease presentation are well documented, the mechanisms mediating vulnerability or resilience to diseases are unknown. In utero insults are more likely to produce detrimental health outcomes for males versus females. In our mouse model of prenatal stress, male offspring experience long-term dysregulation of body weight and hypothalamic pituitary adrenal stress axis dysfunction, endophenotypes of male-biased neurodevelopmental disorders. Placental function is critical for healthy fetal development, and we previously showed that sex differences in placental O-linked N-acetylglucosamine transferase (OGT) mediate the effects of prenatal stress on neurodevelopmental programming. Here we show that one mechanism whereby sex differences in OGT confer variation in vulnerability to prenatal insults is by establishing sex-specific trophoblast gene expression patterns and via regulation of the canonically repressive epigenetic modification, H3K27me3. We demonstrate that high levels of H3K27me3 in the female placenta create resilience to the altered hypothalamic programming associated with prenatal stress exposure.

Highlights

Sex biases in disease presentation are well documented, the mechanisms mediating vulnerability or resilience to diseases are unknown
Consonant with this idea and with the established role for O-linked N-acetylglucosamine transferase (OGT) in regulating epigenetic processes controlling large gene sets, we found that genetic reduction of O-linked N-acetylglucosamine transferase (Ogt) in female trophoblasts (Xogt−/Xwt, Supplementary Figure 2) recapitulated patterns of male (Xwt/Y) trophoblast gene expression compared to wild-type females (Xwt/Xwt; Fig. 1a, c, d) and eliminated many sex differences in trophoblast gene expression compared to wildtype males (Xwt/Y; Fig. 1b, c, d)
This finding corresponds with our data that males and female trophoblasts differ in their epigenomic programming due to differences in placental Ogt dosage and may indicate that placental OGT-mediated epigenomic programing promotes greater baseline homogeneity in female trophoblast gene expression relative to males

Summary

Introduction

Sex biases in disease presentation are well documented, the mechanisms mediating vulnerability or resilience to diseases are unknown. Placental function is critical for healthy fetal development, and we previously showed that sex differences in placental O-linked N-acetylglucosamine transferase (OGT) mediate the effects of prenatal stress on neurodevelopmental programming. Males are more sensitive to prenatal insults, such as gestational stress, maternal infection, and drug exposure, which impart metabolic, cognitive, and behavioral deficits in boys and an increased lifetime risk for disease presentation[7] These statistics support the likelihood that the prenatal environment imparts sex-specific, long-term health consequences whereby males are at greater risk for detrimental outcomes following in utero perturbations. Significant differences in Ogt levels have the potential to determine sex-specific programs of trophoblast gene expression that may mediate sex differences in placental function and trans-placental signals relaying information regarding prenatal insults to the developing fetus. OGT and Ezh2-mediated changes in placental H3K27me[3] may underlie large-scale sex differences and responses to prenatal perturbations, such as stress, by providing tighter control of transcriptional repression in one sex over the other

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