title: Prenatal maternal stress and wheeze in children: novel insights into epigenetic regulation.
abstract: Psychological stress during pregnancy increases the risk of childhood wheeze and asthma. However, the transmitting mechanisms remain largely unknown. Since epigenetic alterations have emerged as a link between perturbations in the prenatal environment and an increased disease risk we used whole genome bisulfite sequencing (WGBS) to analyze changes in DNA methylation in mothers and their children related to prenatal psychosocial stress and assessed its role in the development of wheeze in the child. We evaluated genomic regions altered in their methylation level due to maternal stress based of WGBS data of 10 mother-child-pairs. These data were complemented by longitudinal targeted methylation and transcriptional analyses in children from our prospective mother-child cohort LINA for whom maternal stress and wheezing information was available (n = 443). High maternal stress was associated with an increased risk for persistent wheezing in the child until the age of 5. Both mothers and children showed genome-wide alterations in DNA-methylation specifically in enhancer elements. Deregulated neuroendocrine and neurotransmitter receptor interactions were observed in stressed mothers and their children. In children but not in mothers, calcium- and Wnt-signaling required for lung maturation in the prenatal period were epigenetically deregulated and could be linked with wheezing later in children's life.
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig-UFZ, Permoserstraße 15, Leipzig, 04318, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Trump
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.|Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 267, Heidelberg, 69120, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bieg
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.|Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 267, Heidelberg, 69120, Germany.
authors.forename: Zuguang
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig-UFZ, Permoserstraße 15, Leipzig, 04318, Germany.
authors.forename: Loreen
authors.initials: L
authors.lastname: Thürmann
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bauer
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig-UFZ, Permoserstraße 15, Leipzig, 04318, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.|Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 267, Heidelberg, 69120, Germany.
authors.forename: Naveed
authors.initials: N
authors.lastname: Ishaque
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig-UFZ, Permoserstraße 15, Leipzig, 04318, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Röder
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.|Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig-UFZ, Permoserstraße 15, Leipzig, 04318, Germany.
authors.forename: Gunda
authors.initials: G
authors.lastname: Herberth
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Lawerenz
authors.affiliation: Municipal Hospital "St. Georg" Children's Hospital, Delitzscher Straße 141, 04129 Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Borte
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlesner
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
authors.forename: Nicolle
authors.initials: N
authors.lastname: Diessl
authors.affiliation: Division of Endocrinology and Nephrology, University of Leipzig, Liebigstraße 21, Leipzig, 04103, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Eszlinger
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mücke
authors.affiliation: Department of Urban and Environmental Sociology, Helmholtz Centre for Environmental Research Leipzig-UFZ, Permoserstraße 15, Leipzig, 04318, Germany.
authors.forename: Horst-Dietrich
authors.initials: HD
authors.lastname: Elvers
authors.affiliation: Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, 04318, Leipzig, Germany.
authors.forename: Dirk K
authors.initials: DK
authors.lastname: Wissenbach
authors.affiliation: Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, 04318, Leipzig, Germany.|Faculty of Biosciences, Pharmacy, and Psychology, University of Leipzig, 04318, Leipzig, Germany.|Department of Chemistry and Biosciences, Aalborg University, DK-9220 Aalborg, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: von Bergen
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.|Institute of Pharmacy and Molecular Biotechnology, and Bioquant Center, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg, 69120, Germany.
authors.forename: Carl
authors.initials: C
authors.lastname: Herrmann
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: Department of Pediatrics, Kravis Children's Hospital, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Rosalind J
authors.initials: RJ
authors.lastname: Wright
authors.affiliation: Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig-UFZ, Permoserstraße 15, Leipzig, 04318, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Lehmann
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.|Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 267, Heidelberg, 69120, Germany.|Institute of Pharmacy and Molecular Biotechnology, and Bioquant Center, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg, 69120, Germany.|Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, 69120, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
mesh_terms: D000328:Adult; D002675:Child, Preschool; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D012135:Respiratory Sounds; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism*