title: DNA methylation signatures link prenatal famine exposure to growth and metabolism.
abstract: Periconceptional diet may persistently influence DNA methylation levels with phenotypic consequences. However, a comprehensive assessment of the characteristics of prenatal malnutrition-associated differentially methylated regions (P-DMRs) is lacking in humans. Here we report on a genome-scale analysis of differential DNA methylation in whole blood after periconceptional exposure to famine during the Dutch Hunger Winter. We show that P-DMRs preferentially occur at regulatory regions, are characterized by intermediate levels of DNA methylation and map to genes enriched for differential expression during early development. Validation and further exploratory analysis of six P-DMRs highlight the critical role of gestational timing. Interestingly, differential methylation of the P-DMRs extends along pathways related to growth and metabolism. P-DMRs located in INSR and CPT1A have enhancer activity in vitro and differential methylation is associated with birth weight and serum LDL cholesterol. Epigenetic modulation of pathways by prenatal malnutrition may promote an adverse metabolic phenotype in later life.
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Elmar W
authors.initials: EW
authors.lastname: Tobi
authors.affiliation: Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Jelle J
authors.initials: JJ
authors.lastname: Goeman
authors.affiliation: Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Ramin
authors.initials: R
authors.lastname: Monajemi
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Hongcang
authors.initials: H
authors.lastname: Gu
authors.affiliation: Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Yanju
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Roderick C
authors.initials: RC
authors.lastname: Slieker
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Stok
authors.affiliation: 1] Molecular Epidemiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands [2] Human Genetics, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Thijssen
authors.affiliation: Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.affiliation: Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Erik W
authors.initials: EW
authors.lastname: van Zwet
authors.affiliation: 1] Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany [2] CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, 1090 Vienna, Austria [3] Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
authors.affiliation: 1] The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Stem cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.affiliation: 1] Molecular Epidemiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands [2] Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Lumey
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Eline Slagboom
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
authors.forename: Bastiaan T
authors.initials: BT
authors.lastname: Heijmans
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001724:Birth Weight; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D047109:Fetal Development; D048070:Fetal Nutrition Disorders / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009426:Netherlands; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D013217:Starvation
chemical_list: D015703:Antigens, CD; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase; C435941:INSR protein, human; D011972:Receptor, Insulin