Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio

Iris Bekkering, Mariëtte Leeuwerke, Jozien C. Tanis, Mirthe H. Schoots, Rikst Nynke Verkaik-Schakel, Torsten Plösch, Caterina M. Bilardo, Jasper J. H. Eijsink, Arend F. Bos, Sicco A. Scherjon

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Abstract

Background In Fetal Growth Restriction ‘fetal programming’ may take place via DNA methylation, which has implications for short-term and long-term health outcomes. Small-for-gestational age fetuses are considered fetal growth restricted, characterized by brain-sparing when fetal Doppler hemodynamics are abnormal, expressed as a cerebroplacental ratio (CPR) <1. We aimed to determine whether brain-sparing is associated with altered DNA methylation of selected genes. Methods We compared DNA methylation of six genes in 41 small-for-gestational age placentas with a normal or abnormal CPR. We selected EPO, HIF1A, VEGFA, LEP, PHLDA2, and DHCR24 for their role in angiogenesis, immunomodulation, and placental and fetal growth. DNA methylation was analyzed by pyrosequencing. Results Growth restricted fetuses with an abnormal CPR showed hypermethylation of the VEGFA gene at one CpG (VEGFA-309, p = .001) and an overall hypomethylation of the LEP gene, being significant at two CpGs (LEP-123, p = .049; LEP-51, p = .020). No differences in methylation were observed for the other genes. Conclusions VEGFA and LEP genes are differentially methylated in placentas of small-for-gestational age fetuses with brain-sparing. Hypermethylation of VEGFA-309 in abnormal CPR-placentas could indicate successful compensatory mechanisms. Methylation of LEP-51 is known to suppress LEP expression. Hypomethylation in small-for-gestational age placentas with abnormal CPR may result in hyperleptinemia and predispose to leptin-resistance later in life.
Original languageEnglish
Article numbere0221972
JournalPLoS ONE
Volume14
Issue number8
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

Cite this

Bekkering, I., Leeuwerke, M., Tanis, J. C., Schoots, M. H., Verkaik-Schakel, R. N., Plösch, T., ... Scherjon, S. A. (2019). Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio. PLoS ONE, 14(8), [e0221972]. https://doi.org/10.1371/journal.pone.0221972