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  • Placental insufficiency is regarded as the main etiology for

    2021-04-08

    Placental insufficiency is regarded as the main etiology for FGR. Placental development is highly unique in eutherians and is regulated by numerous factors. For example, the novel retrotransposon-derived gene retrotransposon-like 1 (RTL1) was recently shown to play a key role in placental development.11, 12, 13 RTL1 is a paternally expressed imprinted gene located on human chromosome 14, which is highly expressed during late pregnancy in both the fetus and placenta. Intriguingly, RTL1 GSK1904529A levels are regulated by DNA methylation in its promoter regions. In this study, we hypothesized that the DNA methylation status of RTL1 promoter regions would vary between healthy placentas and those of non-syndromic severe SGA fetuses.
    Materials and methods
    Discussion Although the development of SGA caused by FGR is strongly associated with placental insufficiencies such as aberrant vasculature and malpositioning, the etiology and severity of SGA is heterogeneous and varied. Moreover, the definition of SGA is also variously defined as a BW below the 10th percentile and more than −1.5 SD of the AGA. In this study, we postulated that placental insufficiency caused by aberrant RTL1 expression might result in marked FGR. To exclude incidental or non-pathologic SGA, we selected strict inclusion criteria of more than –2SD of the mean BW, and we defined severe SGA as more than –3SD of the mean BW. Interestingly, the incidence of pregnancy-induced hypertension was higher in the SGA group than in the severe SGA group, suggesting that the etiology of the latter is associated with placental pathologic conditions rather than complications of maternal hypertensive disorders. We found that infants with severe SGA had a higher incidence of abnormal CpG1 methylation in the placenta, though there was no significant difference in the average methylation of each CpG site among the three groups. It is noteworthy that not only hypomethylation but also hypermethylation were predominant in CpG1 of the severe SGA placenta. As a counterpart of paternally expressed RTL1, the maternally expressed RTL1 antisense transcript overlaps and targets the RTL1 transcript through an RNA interference mechanism. Rtl1 null pregnant mice were previously shown to suffer from placental hypoplasia, while pregnant mice overexpressing Rtl1 demonstrated placental hyperplasia. Moreover, fetuses and newborns of both genotypes showed severe pre- and postnatal growth restriction, resulting in fatal outcomes.11, 17 Thus, we speculated that not only placental CpG1 hypomethylation but also hypermethylation at this site would result in fetal growth restriction via abnormal placental formation. It was recently reported that the placental DNA methylation pattern in RTL1 promoter regions was negatively correlated with BW gain at 1 year of age in healthy term infants, suggesting that abnormal RTL1 methylation may affect future life and could be the trigger of DOHaD. A limitation of this study was that we failed to measure RTL1 expression levels in our placental samples. Because RNA degradation of clinical placenta samples occurs rapidly, it is difficult to extract intact RNA from samples originally used for DNA extraction. Additionally, the quantitative analysis of RTL1 that is exclusively of a paternal origin is technically challenging, requiring the 3′ rapid amplification of cDNA ends technique. Therefore, further study to confirm the RTL1 expression profile using intact RNA is warranted. Moreover, because of the technical limitations of pyro-sequencing, we could not survey entire CpG islands in the promoter regions of RTL1. A confirmation study using a high-throughput technique such as methylation-specific microarray or chromatin immunoprecipitation is therefore necessary. In conclusion, infants with severe SGA have abnormal placental DNA methylation of CpG1 in the CG4 region of RTL1, suggesting disturbed epigenetic control in utero. This might contribute to extrauterine growth restriction or the future development of DOHaD in these infants.