Maternal tobacco use modestly alters correlated epigenome-wide placental DNA methylation and gene expression

TLDR

Placental epigenome dysregulation has been linked to pregnancy disorders and long‑term disease risk. The study aimed to correlate genome‑wide placental promoter methylation with gene expression. The authors used Illumina HG‑12 transcription arrays and Infinium 27K methylation arrays to assess genome‑wide correlations between placental gene expression and DNA methylation in smokers versus non‑smokers. Maternal smoking modestly altered placental DNA methylation and gene expression, with 438 genes showing strong methylation‑expression correlations in smokers versus 25 in non‑smokers, and six CpG sites linked to reduced birth weight.

Abstract

Several studies linking alterations in differential placental methylation with pregnancy disorders have implicated (de)regulation of the placental epigenome with fetal programming and later-in-life disease. We have previously demonstrated that maternal tobacco use is associated with alterations in promoter methylation of placental CYP1A1 and that these changes are correlated with CYP1A1 gene expression and fetal growth restriction. In this study we sought to expand our analysis of promoter methylation by correlating it to gene expression on a genome-wide scale. Employing side-by-side IlluminaHG-12 gene transcription with Infinium27K methylation arrays, we interrogated correlative changes in placental gene expression and DNA methylation associated with maternal tobacco smoke exposure at an epigenome-wide level and in consideration of signature gene pathways. We observed that the expression of 623 genes and the methylation of 1024 CpG dinucleotides are significantly altered among smokers, with only 38 CpGs showing significant differential methylation (differing by a methylation level of ≥ 10%). We identified a significant Pearson correlation (≥ 0.7 or ≤ -0.7) between placental transcriptional regulation and differential CpG methylation in only 25 genes among non-smokers but in 438 genes among smokers (18-fold increase, p < 0.0001), with a dominant effect among oxidative stress pathways. Differential methylation at as few as 6 sites was attributed to maternal smoking-mediated birth weight reduction in linear regression models with Bonferroni correction (p < 1.8x10-6). These studies suggest that a common perinatal exposure (such as maternal smoking) deregulates placental methylation in a CpG site-specific manner that correlates with meaningful alterations in gene expression along signature pathways.