Immediate and durable effects of maternal tobacco consumption alter placental DNA methylation in enhancer and imprinted gene-containing regions.
DNA methylation
Epigenome-wide association study
Molecular epidemiology
Placenta
Pregnancy
Smoking
Journal
BMC medicine
ISSN: 1741-7015
Titre abrégé: BMC Med
Pays: England
ID NLM: 101190723
Informations de publication
Date de publication:
07 10 2020
07 10 2020
Historique:
received:
06
02
2020
accepted:
06
08
2020
entrez:
7
10
2020
pubmed:
8
10
2020
medline:
23
2
2021
Statut:
epublish
Résumé
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. 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. 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 (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. 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.
Sections du résumé
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 (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.
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.
Identifiants
pubmed: 33023569
doi: 10.1186/s12916-020-01736-1
pii: 10.1186/s12916-020-01736-1
pmc: PMC7542140
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
306Subventions
Organisme : Institut National Du Cancer
ID : INCa_13641
Pays : International
Organisme : Agence Nationale de la Recherche
ID : ANR-18-CE36-0005
Pays : International
Organisme : Agence Nationale de la Recherche
ID : ANR-13-CESA-0011
Pays : International
Organisme : aviesan
ID : ISP09_2014
Pays : International
Organisme : Fondation de France
ID : 2012-00031593
Pays : International
Organisme : Fondation de France
ID : 2012-00031617
Pays : International
Investigateurs
I Annesi-Maesano
(I)
J Y Bernard
(JY)
J Botton
(J)
M-A Charles
(MA)
P Dargent-Molina
(P)
B de Lauzon-Guillain
(B)
P Ducimetière
(P)
M de Agostini
(M)
B Foliguet
(B)
A Forhan
(A)
X Fritel
(X)
A Germa
(A)
V Goua
(V)
R Hankard
(R)
B Heude
(B)
M Kaminski
(M)
B Larroque
(B)
N Lelong
(N)
J Lepeule
(J)
G Magnin
(G)
L Marchand
(L)
C Nabet
(C)
F Pierre
(F)
R Slama
(R)
M J Saurel-Cubizolles
(MJ)
M Schweitzer
(M)
O Thiebaugeorges
(O)
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