Abstract
Despite the ever-rising incidence of Gestational Diabetes Mellitus (GDM) and its implications for long-term health of mothers and offspring, the underlying molecular mechanisms remain to be elucidated. To contribute to this, the present study’s objectives are to conduct a sex-specific analysis of active histone modifications in placentas affected by GDM and to investigate the effect of calcitriol on trophoblast cell’s transcriptional status. The expression of Histone H3 lysine 9 acetylation (H3K9ac) and Histone H3 lysine 4 trimethylation (H3K4me3) was evaluated in 40 control and 40 GDM (20 male and 20 female each) placentas using immunohistochemistry and immunofluorescence. The choriocarcinoma cell line BeWo and primary human villous trophoblast cells were treated with calcitriol (48 h). Thereafter, western blots were used to quantify concentrations of H3K9ac and the transcription factor FOXO1. H3K9ac expression was downregulated in GDM placentas, while H3K4me3 expression was not significantly different. Cell culture experiments showed a slight downregulation of H3K9ac after calcitriol stimulation at the highest concentration. FOXO1 expression showed a dose-dependent increase. Our data supports previous research suggesting that epigenetic dysregulations play a key role in gestational diabetes mellitus. Insufficient transcriptional activity may be part of its pathophysiology and this cannot be rescued by calcitriol.
Highlights
Gestational Diabetes Mellitus (GDM) is defined as glucose intolerance firstly detected during pregnancy [1]
H3K9ac enrichment, on the other hand, marks active enhancers. Both Post-translational Modification (PTM) are found at bivalent promoters marking regulatory genes of importance for cell differentiation [26,29]. These findings indicate that both H3K9ac and H3K4me3, like epigenetics in general, are of great importance for an organism’s development and human disease
We found H3K9ac to be upregulated in syncytiotrophoblast, extra villous trophoblast (EVT), as well as foetal endothelial cells in GDM placentas
Summary
Gestational Diabetes Mellitus (GDM) is defined as glucose intolerance firstly detected during pregnancy [1]. It is the most common pregnancy-related metabolic disorder, affecting up to 14% of pregnancies [2]. Women who suffered from GDM stand a substantially higher risk of developing diabetes mellitus type 2 (DM2) later in life (relative risk (RR) 7.43) [7]. Their offspring suffer from a higher risk for developing metabolic syndrome, DM2, adiposity and cardiovascular disease [8,9,10]
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