**4. Perspectives and Conclusions**

The recent years have seen the emergence of an increasing number of studies focused on the role of epigenetics in the regulation of placental development and on its potential implication in placental pathologies. However, we still lack a precise picture on how these epigenetic modifications correlate with gene expression. In particular, we have a limited knowledge on how DNA-methylation or Histone modifications impact gene expression in normal and pathological placenta development. In addition, our knowledge on the mechanisms regulating the dynamics of the instauration of the di fferent epigenetic marks across development is very scarce. Nevertheless, recent studies have started to reveal how epigenetics is involved in the regulation of important processes in placental development such as cell fate determination, *syncytialization* or EVT migration and invasion. The emergence of new technologies allowing the study of the epigenetic and transcriptomic profiles of the di fferent cells types of the placenta will certainly greatly contribute to improve our understanding of epigenetics in placenta. Moreover, in the context of PE, to date, the studies analyzing epigenetic modifications have focused on the placenta, however the antiangiogenic and cytotoxic factors released by the PE placenta have the potential to induce epigenetics modifications in maternal target tissues (blood cells, endothelial cells). This could impact the future maternal and fetal health and deserves to be studied in detail. Overall, the comprehension of epigenetic regulation in preeclampsia both at the level of the placenta and other involved organs could provide new biomarkers and therapeutic targets to improve the managemen<sup>t</sup> of this disease. For the moment, this has not been successfully applied as diagnostic or prognostic of preeclampsia. One explanation of this observation could be that the extraction of circulating RNAs from the plasma is still immature technologically, leading to discrepant results between various laboratories and absence of consensus in defining a panel of diagnostic miRNA. This may evolve in the future, leading to substantial exploitation of these markers in complex diseases, including preeclampsia.

**Supplementary Materials:** Supplementary materials can be found at http://www.mdpi.com/1422-0067/20/11/ 2837/s1. Table S1. High-throughput studies analyzing methylation profiles of di fferent relevant tissues in the context of preeclampsia [42,43,47,54–73].

**Funding:** F.M., C.M. and D.V. are funded by INSERM, C.S.M.R. and C.A. are PhD students, funded by the H2020 European project 'iPLACENTA,' headed by Colin Murdoch.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
