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Expression of epigenetic machinery genes is sensitive to maternal obesity and weight loss in relation to fetal growth in mice
Univ Paris Saclay, UMR BDR, INRA, ENVA, F-78350 Jouy En Josas, France;Univ Paris 06, Ecole Doctorale Physiol Physiopathol & Therapeut, F-75252 Paris, France.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Biologie du Developpement et Reproduction, INRA, Jouy-en-Josas. (Functional Pharmacology)
Univ Paris Saclay, UMR BDR, INRA, ENVA, F-78350 Jouy En Josas, France.
Univ Paris Saclay, UMR BDR, INRA, ENVA, F-78350 Jouy En Josas, France.
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2016 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 8, 22Article in journal (Refereed) Published
Abstract [en]


Maternal obesity impacts fetal growth and pregnancy outcomes. To counteract the deleterious effects of obesity on fertility and pregnancy issue, preconceptional weight loss is recommended to obese women. Whether this weight loss is beneficial/detrimental for offspring remains poorly explored. Epigenetic mechanisms could be affected by maternal weight changes, perturbing expression of key developmental genes in the placenta or fetus. Our aim was to investigate the effects of chronic maternal obesity on feto-placental growth along with the underlying epigenetic mechanisms. We also tested whether preconceptional weight loss could alleviate these effects.


Female mice were fed either a control diet (CTRL group), a high-fat diet (obese (OB) group), or a high-fat diet switched to a control diet 2 months before conception (weight loss (WL) group). At mating, OB females presented an obese phenotype while WL females normalized metabolic parameters. At embryonic day 18.5 (E18.5), fetuses from OB females presented fetal growth restriction (FGR; -13 %) and 28 % of the fetuses were small for gestational age (SGA). Fetuses from WL females normalized this phenotype. The expression of 60 epigenetic machinery genes and 32 metabolic genes was measured in the fetal liver, placental labyrinth, and junctional zone. We revealed 23 genes altered by maternal weight trajectories in at least one of three tissues. The fetal liver and placental labyrinth were more responsive to maternal obesity than junctional zone. One third (18/60) of the epigenetic machinery genes were differentially expressed between at least two maternal groups. Interestingly, genes involved in the histone acetylation pathway were particularly altered (13/18). In OB group, lysine acetyltransferases and Bromodomain-containing protein 2 were upregulated, while most histone deacetylases were downregulated. In WL group, the expression of only a subset of these genes was normalized.


This study highlights the high sensitivity of the epigenetic machinery gene expression, and particularly the histone acetylation pathway, to maternal obesity. These obesity-induced transcriptional changes could alter the placental and the hepatic epigenome, leading to FGR. Preconceptional weight loss appears beneficial to fetal growth, but some effects of previous obesity were retained in offspring phenotype.

Place, publisher, year, edition, pages
2016. Vol. 8, 22
Keyword [en]
Maternal obesity; Preconceptional weight loss; Fetal growth restriction; Epigenetic machinery; Histone deacetylases (HDACs); Lysine acetyltransferases (KATs); Placenta; Liver
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
URN: urn:nbn:se:uu:diva-300748DOI: 10.1186/s13148-016-0188-3ISI: 000371288600001PubMedID: 26925174OAI: oai:DiVA.org:uu-300748DiVA: diva2:952269
Available from: 2016-08-12 Created: 2016-08-12 Last updated: 2016-09-05Bibliographically approved
In thesis
1. Bioinformatic and Biostatistic Analysis of Epigenetic Data from Humans and Mice in the Context of Obesity and its Complications
Open this publication in new window or tab >>Bioinformatic and Biostatistic Analysis of Epigenetic Data from Humans and Mice in the Context of Obesity and its Complications
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Worldwide obesity has more than doubled since 1980 and at least 2.8 million people die each year as a result of being overweight or obese. An elevated body weight is the result of the interplay between susceptibility gene variants and an obesogenic environment, and recent evidence shows that epigenetic processes are likely involved. The growing availability of high-throughput technologies has made it possible to assess quickly the entire epigenome of large samples at a relatively low cost. As a result, vast amounts of data have been generated and researchers are now confronted to both bioinformatic and biostatistic challenges to make sense of such data in the context of obesity and its complications. In this doctoral thesis, we explored associations between the human blood methylome and obesity-associated gene variants as well as dietary fat quality and quantity. We used well described preprocessing techniques and statistical methods, along with publicly available data from consortiums and other research groups, as well as tools for pathway enrichment and chromatin state inference. We found associations between obesityassociated SNPs and methylation levels at proximal promoters and enhancers, and some of these associations were replicated in multiple tissues. We also found that contrary to dietary fat quantity, dietary fat quality associates with methylation levels in the promoter of genes involved in metabolic pathways. Then, using a gene-targeted approach, we looked at the impact of an acute environmental stress (sleep loss) on the methylation and transcription levels of circadian clock genes in skeletal muscle and adipose tissue of healthy men. We found that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in a tissue-specific manner. Finally, we looked at the effects of chronic maternal obesity and subsequent weight loss on the transcription of epigenetic machinery genes in the fetus and placenta of mice. We found that the transcription of epigenetic machinery genes is highly sensitive to maternal weight trajectories, and particularly those of the histone acetylation pathway. Overall, this thesis demonstrated that genetics, obesogenic environment stimuli and maternal programming impact epigenetic marks at genomic locations relevant in the pathogenesis of obesity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 143 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1245
obesity, genetics, epigenetics, DNA methylation, sleep, developmental origins of health and disease, single nucleotide polymorphism, genome-wide association study
National Category
Medical Genetics Nutrition and Dietetics Genetics
urn:nbn:se:uu:diva-300751 (URN)978-91-554-9655-5 (ISBN)
Public defence
2016-09-22, C8:301, BMC, Husargatan 3, Uppsala, 13:00 (English)
Available from: 2016-08-31 Created: 2016-08-12 Last updated: 2016-09-21

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