Dataset Information

Immediate and durable effects of maternal tobacco consumption alter placental DNA methylation in enhancer and imprinted gene-containing regions.

ABSTRACT:

Background

Although exposure to cigarette smoking during pregnancy has been associated with alterations of DNA methylation in the cord blood or placental cells, whether such exposure before pregnancy could induce epigenetic alterations in the placenta of former smokers has never been investigated.

Methods

Our approach combined the analysis of placenta epigenomic (ENCODE) data with newly generated DNA methylation data obtained from 568 pregnant women, the largest cohort to date, either actively smoking during their pregnancy or formerly exposed to tobacco smoking.

Results

This strategy resulted in several major findings. First, among the 203 differentially methylated regions (DMRs) identified by the epigenome-wide association study, 152 showed "reversible" alterations of DNA methylation, only present in the placenta of current smokers, whereas 26 were also found altered in former smokers, whose placenta had not been exposed directly to cigarette smoking. Although the absolute methylation changes were smaller than those observed in other contexts, such as in some congenital diseases, the observed alterations were consistent within each DMR. This observation was further supported by a demethylation of LINE-1 sequences in the placentas of both current (beta-coefficient (?) (95% confidence interval (CI)), -?0.004 (-?0.008; 0.001)) and former smokers (? (95% CI), -?0.006 (-?0.011; -?0.001)) compared to nonsmokers. Second, the 203 DMRs were enriched in epigenetic marks corresponding to enhancer regions, including monomethylation of lysine 4 and acetylation of lysine 27 of histone H3 (respectively H3K4me1 and H3K27ac). Third, smoking-associated DMRs were also found near and/or overlapping 10 imprinted genes containing regions (corresponding to 16 genes), notably including the NNAT, SGCE/PEG10, and H19/MIR675 loci.

Conclusions

Our results pointing towards genomic regions containing the imprinted genes as well as enhancers as preferential targets suggest mechanisms by which tobacco could directly impact the fetus and future child. The persistence of significant DNA methylation changes in the placenta of former smokers supports the hypothesis of an "epigenetic memory" of exposure to cigarette smoking before pregnancy. This observation not only is conceptually revolutionary, but these results also bring crucial information in terms of public health concerning potential long-term detrimental effects of smoking in women.

SUBMITTER: Rousseaux S

PROVIDER: S-EPMC7542140 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Immediate and durable effects of maternal tobacco consumption alter placental DNA methylation in enhancer and imprinted gene-containing regions.

Rousseaux Sophie S Seyve Emie E Chuffart Florent F Bourova-Flin Ekaterina E Benmerad Meriem M Charles Marie-Aline MA Forhan Anne A Heude Barbara B Siroux Valérie V Slama Remy R Tost Jorg J Vaiman Daniel D Khochbin Saadi S Lepeule Johanna J

BMC medicine 20201007 1

<h4>Background</h4>Although exposure to cigarette smoking during pregnancy has been associated with alterations of DNA methylation in the cord blood or placental cells, whether such exposure before pregnancy could induce epigenetic alterations in the placenta of former smokers has never been investigated.<h4>Methods</h4>Our approach combined the analysis of placenta epigenomic (ENCODE) data with newly generated DNA methylation data obtained from 568 pregnant women, the largest cohort to date, ei ...[more]

PMID: 33023569

Similar Datasets

Project description:BackgroundPlacental mesenchymal dysplasia (PMD) is a morphological abnormality resembling partial hydatidiform moles. It is often associated with androgenetic/biparental mosaicism (ABM) and complicated by Beckwith-Wiedemann syndrome (BWS), an imprinting disorder. These phenomena suggest an association between PMD and aberrant genomic imprinting, particularly of CDKN1C and IGF2. The existence of another type of PMD containing the biparental genome has been reported. However, the frequency and etiology of biparental PMD are not yet fully understood.ResultsWe examined 44 placental specimens from 26 patients with PMD: 19 of these were macroscopically normal and 25 exhibited macroscopic PMD. Genotyping by DNA microarray or short tandem repeat analysis revealed that approximately 35% of the macroscopic PMD specimens could be classified as biparental, while the remainder were ABM. We performed a DNA methylation analysis using bisulfite pyrosequencing of 15 placenta-specific imprinted differentially methylated regions (DMRs) and 36 ubiquitous imprinted DMRs. As expected, most DMRs in the macroscopic PMD specimens with ABM exhibited the paternal epigenotype. Importantly, the biparental macroscopic PMD specimens exhibited frequent aberrant hypomethylation at seven of the placenta-specific DMRs. Allelic expression analysis using single-nucleotide polymorphisms revealed that five imprinted genes associated with these aberrantly hypomethylated DMRs were biallelically expressed. Frequent aberrant hypomethylation was observed at five ubiquitous DMRs, including GRB10 but not ICR2 or ICR1, which regulate the expression of CDKN1C and IGF2, respectively. Whole-exome sequencing performed on four biparental macroscopic PMD specimens did not reveal any pathological genetic abnormalities. Clinical and molecular analyses of babies born from pregnancies with PMD revealed four cases with BWS, each exhibiting different molecular characteristics, and those between BWS and PMD specimens were not always the same.ConclusionThese data clarify the prevalence of biparental PMD and ABM-PMD and strongly implicate hypomethylation of DMRs in the pathogenesis of biparental PMD, particularly placenta-specific DMRs and the ubiquitous GRB10, but not ICR2 or ICR1. Aberrant hypomethylation of DMRs was partial, indicating that it occurs after fertilization. PMD is an imprinting disorder, and it may be a missing link between imprinting disorders and placental disorders incompatible with life, such as complete hydatidiform moles and partial hydatidiform moles.

Dataset Information

Immediate and durable effects of maternal tobacco consumption alter placental DNA methylation in enhancer and imprinted gene-containing regions.

Background

Methods

Results

Conclusions

Publications

Immediate and durable effects of maternal tobacco consumption alter placental DNA methylation in enhancer and imprinted gene-containing regions.

Similar Datasets

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