br Author contribution br Acknowledgements QNRF grant

Author contribution
Acknowledgements QNRF grant number NPRP6-065-3-012, Qatar National Research Fund, Doha Qatar for funding this work with grant number NPRP No.: NPRP6-065-3-012.
Introduction Preeclampsia (PE) affects 3–5 % of pregnancies worldwide and is one of the leading causes of maternal and fetal morbidity and mortality [1]. PE is characterized by the onset of maternal hypertension and increased urinary protein secretion after 20 weeks of gestation [2]. Several theories (e.g., immunological, placental ischemia, and genetic) have been described to explain PE pathogenesis; however, to date, no unifying characteristic accounts for the vast numbers of risk factors associated with this disease [3]. Although there are many underlying causes of PE, in general, it is agreed that one of the origins of PE is the placenta because the only cure for PE is the end of the complete pregnancy when the placenta is removed, after which the symptoms regress rapidly [4]. Recently, we identified decreased expression of 14-3-3 tau, whose corresponding gene name is YWHAQ, in a hypoxia-treated human trophoblast cell line BeWo using proteomic analysis [5]. Additionally, 14-3-3 tau markedly expressing in cytotrophoblast cells in placental villi, might mediate trophoblast differentiation through Tolvaptan chemical regulation [6]. The 14-3-3 proteins are 30-kDa homodimers and have seven isoforms [7]. Several isoforms of 14-3-3 are considered to be relevant in the functional regulation of trophoblasts. For example, 14-3-3ε (YWHAE), detected in the first trimester human cytotrophoblast, plays a functional role in cellular responses to reduced oxygen levels [8]. In preeclamptic placentas, the level of 14-3-3ζ (YWHAZ) is significantly higher compared with normal placentas [9]. Therefore, we are interested in the placental expression of 14-3-3 tau in PE patients. The epigenetic regulation of placental genes has been implicated in the onset of placenta-mediated disorders, including PE [10]. An examination of the human placental epigenome is therefore critical to understand its unique function and potential role in PE. The major areas of epigenetics include DNA methylation, histone modifications, and genomic imprinting. Placenta-specific methylation patterns have been demonstrated in PE placenta and maternal plasma [11], [12]. Genomic DNA methylation occurs predominantly on the 5th carbon atom of cytosine (5-methylcytosine (5 mC)) in the context of CpG islands in mammals, and it has a broad and important role in normal development and tumor suppression [13]. The ten-eleven translocation (TET) family of α-ketoglutarate (α-KG)-dependent dioxygenases catalyzes the sequential oxidation of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC), 5-formylcytosine and 5-carboxylcytosine, which eventually leads to DNA demethylation. Several studies have reported that the levels of 5 hmC in various human cancers were strongly reduced compared with the corresponding normal tissue surrounding the tumor [14], [15], [16], [17], [18], while several studies have detected lower levels of TET gene expression in cancer [17], [18]. Furthermore, Koh et al. found that TET regulates 5 hmC production and cell lineage specification in mouse embryonic stem cells [19]. Though there have been numerous microarrays probing for TET1, 2 and 3 in PE tissue [20], [21], [22], they were not reported as significant. In addition, in mouse embryonic stem cell, hydroxymethylase TET1, which is involved in demethylation, strongly binds to the promoter of 14-3-3 theta (YWHAQ) gene in chromatin precipitation-sequencing (ChIP-Seq) analysis, which suggests that TET1 may regulate 14-3-3 theta gene expression through regulating the DNA methylation status at YWHAQ promoter [23]. In fact, 14-3-3 theta/tau is an isoform of 14-3-3 protein, including theta in mice and tau in human. These studies suggest that 14-3-3 tau (YWHAQ) may play a role in epigenetic regulation of placental genes in the onset of PE. Therefore, a search for abnormal methylation (hypo/hyper) patterns of YWHAQ is a reasonable approach to identify new markers involved in PE with the goals of predicting and deciphering PE pathogenesis. There have been methylation array studies which have included probes for YWHAQ in PE tissues, of which the differential methylation has not yet been identified as significant [24].