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

BMC Medicine

Daniel Vaiman¹  Jorg Tost²  Emie Seyve³  Sophie Rousseaux³  Johanna Lepeule³  Florent Chuffart³  Meriem Benmerad³  Saadi Khochbin³  Ekaterina Bourova-Flin³  Valérie Siroux³  Remy Slama³  Barbara Heude⁴  Marie-Aline Charles⁴  Anne Forhan⁴ 

[1] Genomics, Epigenetics and Physiopathology of Reproduction, Institut Cochin, U1016 Inserm – UMR 8104 CNRS – Paris-Descartes University, Paris, France;Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA – Institut de Biologie François Jacob, Evry, France;Université Grenoble Alpes, Inserm, CNRS, IAB, 38000, Grenoble, France;Université de Paris, Centre for Research in Epidemiology and Statistics (CRESS), INSERM, INRAE, Paris, France;

关键词: Placenta;    DNA methylation;    Pregnancy;    Smoking;    Epigenome-wide association study;    Molecular epidemiology;   

DOI  :  10.1186/s12916-020-01736-1

来源: Springer

【 摘 要 】

BackgroundAlthough 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.MethodsOur 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.ResultsThis 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 (β) (95% confidence interval (CI)), − 0.004 (− 0.008; 0.001)) and former smokers (β (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.ConclusionsOur 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.

【 授权许可】

CC BY