Rahat Beenish, Thakur Shilpa, Bagga Rashmi, Kaur Jyotdeep
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
Department of Obstetricsand Gynaecology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
Placenta. 2016 Aug;44:46-53. doi: 10.1016/j.placenta.2016.06.003. Epub 2016 Jun 8.
Development of normal placenta requires regulated apoptosis of trophoblasts. However, uncontrolled apoptosis has been seen in the pregnancy related complications like hydatidiform mole and pre-eclampsia. STAT5A is a transcription factor with well-known anti-apoptotic role. Thus, we sought to study the role of STAT5A and its epigenetic regulation in placental development and pathologies and its use as fetal DNA epigenetic marker.
The present study was conducted on pregnant women who were enrolled in five groups, based on the three trimesters in normal pregnancy and two pregnancy related disorder groups: pre-eclampsia and hydatidiform mole. Placental villi samples and maternal blood were obtained from each pregnant woman and were analyzed for promoter region methylation (via methylation sensitive high resolution melting) and histone trimethylations (via chromatin immunoprecipitation) of STAT5A.
Our data revealed higher expression of STAT5A in first trimester villi, which decreased with advancing gestation with corresponding increased DNA methylation and H3 trimethylations. Development of choriocarcinoma was associated with DNA methylation associated lower expression of STAT5A. The pattern of promoter methylation of STAT5A in cell free DNA within maternal plasma was observed to be similar to its promoter methylation in placental villi during normal pregnancy, pre-eclampsia and molar complications, which suggested its use as a novel fetal DNA epigenetic marker.
Our results suggest the regulation of STAT5A via epigenetic mechanisms during normal pregnancy and the association of STAT5A epigenetic dysregulation in pregnancy related complications. Further, hypermethylated STAT5A can be utilized as novel fetal DNA epigenetic marker.
正常胎盘的发育需要滋养层细胞进行程序性凋亡。然而，在葡萄胎和子痫前期等妊娠相关并发症中，出现了不受控制的细胞凋亡。信号转导和转录激活因子5A（STAT5A）是一种具有众所周知的抗凋亡作用的转录因子。因此，我们试图研究STAT5A及其表观遗传调控在胎盘发育和病理过程中的作用，以及它作为胎儿DNA表观遗传标志物的用途。
本研究对孕妇进行了分组研究，根据正常妊娠的三个孕期分为三组，以及两个妊娠相关疾病组：子痫前期组和葡萄胎组。从每位孕妇获取胎盘绒毛样本和母血，分析STAT5A的启动子区域甲基化（通过甲基化敏感高分辨率熔解分析）和组蛋白三甲基化（通过染色质免疫沉淀分析）情况。
我们的数据显示，STAT5A在孕早期绒毛中的表达较高，随着孕周增加而降低，同时DNA甲基化和H3三甲基化相应增加。绒毛膜癌的发生与DNA甲基化导致的STAT5A低表达有关。观察到母血浆中游离DNA内STAT5A的启动子甲基化模式，与正常妊娠、子痫前期和葡萄胎并发症时胎盘绒毛中的启动子甲基化模式相似，这表明它可作为一种新型胎儿DNA表观遗传标志物。
我们的结果表明，在正常妊娠期间，STAT5A通过表观遗传机制受到调控，并且在妊娠相关并发症中存在STAT5A表观遗传失调的情况。此外，高甲基化的STAT5A可作为新型胎儿DNA表观遗传标志物。
