Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Maistraße 11, 80337 Munich, Germany.
Department of Obstetrics, Klinik Hallerwiese, 90419 Nürnberg, Germany.
Int J Mol Sci. 2018 Dec 14;19(12):4061. doi: 10.3390/ijms19124061.
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.
尽管妊娠糖尿病（GDM）的发病率不断上升，对母婴的长期健康有影响，但潜在的分子机制仍有待阐明。为了对此做出贡献，本研究的目的是对受 GDM 影响的胎盘进行活性组蛋白修饰的性别特异性分析，并研究 1,25-二羟维生素 D3（骨化三醇）对滋养细胞转录状态的影响。使用免疫组织化学和免疫荧光法评估了 40 例对照胎盘和 40 例 GDM 胎盘（男女各 20 例）中组蛋白 H3 赖氨酸 9 乙酰化（H3K9ac）和组蛋白 H3 赖氨酸 4 三甲基化（H3K4me3）的表达。用骨化三醇（48 h）处理绒毛膜癌细胞系 BeWo 和原代人绒毛滋养细胞。然后，使用 Western blot 定量 H3K9ac 和转录因子 FOXO1 的浓度。GDM 胎盘中的 H3K9ac 表达下调，而 H3K4me3 表达无明显差异。细胞培养实验表明，在最高浓度的骨化三醇刺激下，H3K9ac 略有下调。FOXO1 表达呈剂量依赖性增加。我们的数据支持先前的研究，表明表观遗传失调在妊娠糖尿病中起关键作用。转录活性不足可能是其病理生理学的一部分，而骨化三醇不能对此进行挽救。
