title: Environment-induced epigenetic reprogramming in genomic regulatory elements in smoking mothers and their children.
abstract: Epigenetic mechanisms have emerged as links between prenatal environmental exposure and disease risk later in life. Here, we studied epigenetic changes associated with maternal smoking at base pair resolution by mapping DNA methylation, histone modifications, and transcription in expectant mothers and their newborn children. We found extensive global differential methylation and carefully evaluated these changes to separate environment associated from genotype-related DNA methylation changes. Differential methylation is enriched in enhancer elements and targets in particular "commuting" enhancers having multiple, regulatory interactions with distal genes. Longitudinal whole-genome bisulfite sequencing revealed that DNA methylation changes associated with maternal smoking persist over years of life. Particularly in children prenatal environmental exposure leads to chromatin transitions into a hyperactive state. Combined DNA methylation, histone modification, and gene expression analyses indicate that differential methylation in enhancer regions is more often functionally translated than methylation changes in promoters or non-regulatory elements. Finally, we show that epigenetic deregulation of a commuting enhancer targeting c-Jun N-terminal kinase 2 (JNK2) is linked to impaired lung function in early childhood.
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tobias
authors.identifier: http://orcid.org/0000-0002-4961-3639
authors.initials: T
authors.lastname: Bauer
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Trump
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Heidelberg, Germany.
authors.forename: Naveed
authors.initials: N
authors.lastname: Ishaque
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany.
authors.forename: Loreen
authors.initials: L
authors.lastname: Thürmann
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bieg
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Heidelberg, Germany.
authors.forename: Zuguang
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: Research Group Genome Organization & Function, German Cancer Research Center (DKFZ) and Bioquant, Heidelberg, Germany.
authors.forename: Jan-Philipp
authors.initials: JP
authors.lastname: Mallm
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Röder
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany.
authors.forename: Gunda
authors.initials: G
authors.lastname: Herberth
authors.affiliation: Department of Immunology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Eiko
authors.initials: E
authors.lastname: Takada
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mücke
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Winter
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Junge
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Grützmann
authors.affiliation: Department Metabolomics, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Rolle-Kampczyk
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Lawerenz
authors.affiliation: Municipal Hospital "St Georg" Children's Hospital, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Borte
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany Department of Dermatology, Venerology and Allerology, Leipzig University Medical Center, Leipzig, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Polte
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlesner
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schanne
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.affiliation: Sample Processing Lab, National Center for Tumor Disease and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Geörg
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, The Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Research Group Genome Organization & Function, German Cancer Research Center (DKFZ) and Bioquant, Heidelberg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Rippe
authors.affiliation: Department of Immunology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Mizuguchi
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Institute of Pharmacy and Molecular Biotechnology and Bioquant Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Carl
authors.initials: C
authors.lastname: Herrmann
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Heidelberg, Germany Institute of Pharmacy and Molecular Biotechnology and Bioquant Center, University of Heidelberg, Heidelberg, Germany Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany r.eils@dkfz-heidelberg.de irina.lehmann@ufz.de.
authors.forename: Roland
authors.identifier: http://orcid.org/0000-0002-0034-4036
authors.initials: R
authors.lastname: Eils
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany r.eils@dkfz-heidelberg.de irina.lehmann@ufz.de.
authors.forename: Irina
authors.initials: I
authors.lastname: Lehmann
mesh_terms: D002648:Child; D002843:Chromatin / Q000378:metabolism; D015331:Cohort Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics; D009035:Mothers; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012045:Regulatory Sequences, Nucleic Acid; D012907:Smoking / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; D048056:Mitogen-Activated Protein Kinase 9
keywords: WGBS; enhancer deregulation; environment; epigenetics; histone modifications