Epigenetic modifications at DMRs of placental genes are subjected to variations in normal gestation, pathological conditions and folate supplementation

Beenish Rahat,Rashmi Bagga,Abid Hamid,Jyotdeep Kaur,Aatish Mahajan

doi:10.1038/srep40774

Abstract

Invasive placentation and cancer development shares many similar molecular and epigenetic pathways. Paternally expressed, growth promoting genes (SNRPN, PEG10 and MEST) which are known to play crucial role in tumorogenesis, are not well studied during placentation. This study reports for the first time of the impact of gestational-age, pathological conditions and folic acid supplementation on dynamic nature of DNA and histone methylation present at their differentially methylated regions (DMRs). Here, we reported the association between low DNA methylation/H3K27me3 and higher expression of SNRPN, PEG10 and MEST in highly proliferating normal early gestational placenta. Molar and preeclamptic placental villi, exhibited aberrant changes in methylation levels at DMRs of these genes, leading to higher and lower expression of these genes, respectively, in reference to their respective control groups. Moreover, folate supplementation could induce gene specific changes in mRNA expression in placental cell lines. Further, MEST and SNRPN DMRs were observed to show the potential to act as novel fetal DNA markers in maternal plasma. Thus, variation in methylation levels at these DMRs regulate normal placentation and placental disorders. Additionally, the methylation at these DMRs might also be susceptible to folic acid supplementation and has the potential to be utilized in clinical diagnosis.

Highlights

Be associated with defective gene expression[16], leading to poor invasion of endovascular trophoblasts[17,18] and abnormal remodeling of maternal spiral arteries[19]
We analyzed the mRNA expression of three imprinting genes Small nuclear ribonucleoprotein-associated protein N (SNRPN), paternally expressed gene 10 (PEG10) and mesoderm-specific transcript (MEST) in physiological first, second and third trimester groups and placental disorders and JEG-3 cells (Fig. 1A and B)
The mRNA expression of all the three imprinting genes were observed to reduce with gestation, decreasing by 4.4–5.7 fold after midgestation (p < 0.001) in case of SNRPN, while decreasing by 2.3- (p < 0.01) and 3.6- (p < 0.001) folds in second trimester and third trimester respectively for PEG10 and by 3.3 fold (p < 0.05) in third trimester for MEST with respect to first trimester placental villi (Fig. 1A). mRNA estimation of SNRPN, PEG10 and MEST in maternal blood leukocytes revealed non-significant change within normal gestational groups (Fig. 1B)

Summary

Introduction

Be associated with defective gene expression[16], leading to poor invasion of endovascular trophoblasts[17,18] and abnormal remodeling of maternal spiral arteries[19]. MEST is a member of the [α/β] hydrolase fold family and play a prominent role in angiogenesis placental trophoblast and decidua It is highly expressed in the placenta and its loss leads to placental growth restriction[30]. Previous studies from our lab[37] and others have highlighted the importance of epigenetic modifications in regulating the differential expression of various genes in placenta Based on this background information we aimed to analyze the effect of advancing gestation, placental dysfunction and nutritional supplementation on epigenetic mechanisms at the DMRs within the promoter region of SNRPN, PEG10 and MEST and their effect on their relative expression. We investigated the potential of the DMRs of these genes as fetal DNA epigenetic markers in maternal plasma, for their future use in prenatal diagnosis and the diagnosis of pregnancy related disorders

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