Maternal obesity increases DNA methylation and decreases RNA methylation in the human placenta

Abstract

Maternal obesity is associated with increased risk of adverse pregnancy and birth outcomes. While increasing body of evidence supports that the etiology is related to fetal and placental hypoxia, molecular signaling changes in response to this pathophysiological condition in human placenta have remained elusive. Here by using varied approaches including immunocytochemistry staining, Western blot, RT-qPCR, and ELISA, we aimed to investigate the changes in epigenetic markers in placentas from obese pregnant women following delivery by Caesarean-section at term. Our results revealed that the levels of 5-methylcytosine (5mC), a methylated form commonly occurring in CpG dinucleotides and an important repressor of gene transcription in the genome, were significantly increased coupled with decreased activity of Ten-Eleven Translocation (TETs) enzymes that principally function by oxidizing 5mC in the obese placenta, consistent with hypoxia-induced genome-wide DNA hypermethylation observed in varied types of cells and tissues. N6-methyladenosine (m6A) represents the most abundant and conserved modification of gene transcripts, especially within mRNAs, which is stalled by m6A methyltransferases or “writers” including METTL-3/-14, WTAP, RBM15B, and KIAA1429. We further showed that obese placentas demonstrated significantly down-regulated levels of m6A along with reduced gene expression of WTAP, RBM15B, and KIAA1429. Our data support that maternal obesity-induced hypoxia may play an important role in triggering genome-wide DNA hypermethylation in the human placenta, and in turn leading to transcriptome-wide inhibition of RNA modifications. Our results further suggest that selectively modulating these pathways may facilitate development of novel therapeutic approaches for controlling and managing maternal obesity-associated adverse clinical outcomes.