title: Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice.
abstract: The serotonin transporter gene (5-HTT/SLC6A4)-linked polymorphic region has been suggested to have a modulatory role in mediating effects of early-life stress exposure on psychopathology rendering carriers of the low-expression short (s)-variant more vulnerable to environmental adversity in later life. The underlying molecular mechanisms of this gene-by-environment interaction are not well understood, but epigenetic regulation including differential DNA methylation has been postulated to have a critical role. Recently, we used a maternal restraint stress paradigm of prenatal stress (PS) in 5-HTT-deficient mice and showed that the effects on behavior and gene expression were particularly marked in the hippocampus of female 5-Htt+/- offspring. Here, we examined to which extent these effects are mediated by differential methylation of DNA. For this purpose, we performed a genome-wide hippocampal DNA methylation screening using methylated-DNA immunoprecipitation (MeDIP) on Affymetrix GeneChip Mouse Promoter 1.0 R arrays. Using hippocampal DNA from the same mice as assessed before enabled us to correlate gene-specific DNA methylation, mRNA expression and behavior. We found that 5-Htt genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes, a subset of which showed overlap with the expression profiles of the corresponding transcripts. For example, a differentially methylated region in the gene encoding myelin basic protein (Mbp) was associated with its expression in a 5-Htt-, PS- and 5-Htt × PS-dependent manner. Subsequent fine-mapping of this Mbp locus linked the methylation status of two specific CpG sites to Mbp expression and anxiety-related behavior. In conclusion, hippocampal DNA methylation patterns and expression profiles of female prenatally stressed 5-Htt+/- mice suggest that distinct molecular mechanisms, some of which are promoter methylation-dependent, contribute to the behavioral effects of the 5-Htt genotype, PS exposure and their interaction.
authors.affiliation: Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: K G
authors.initials: KG
authors.lastname: Schraut
authors.affiliation: Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: S B
authors.initials: SB
authors.lastname: Jakob
authors.affiliation: 1] Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Wuerzburg, Wuerzburg, Germany [2] Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands.
authors.forename: M T
authors.initials: MT
authors.lastname: Weidner
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: A G
authors.initials: AG
authors.lastname: Schmitt
authors.affiliation: Laboratory for Microarray Applications, Interdisciplinary Center for Clinical Research, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: C J
authors.initials: CJ
authors.lastname: Scholz
authors.affiliation: 1] Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands [2] Institute for Hygiene and Tropical Medicine, New University of Lisbon, Lisbon, Portugal.
authors.forename: T
authors.initials: T
authors.lastname: Strekalova
authors.affiliation: Institute of Human Genetics, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: El Hajj
authors.affiliation: Department of Bioinformatics-BiGCaT, Maastricht University, Maastricht, The Netherlands.
authors.forename: L M T
authors.initials: LM
authors.lastname: Eijssen
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Domschke
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Reif
authors.affiliation: Institute of Human Genetics, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haaf
authors.affiliation: Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Ortega
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands.
authors.forename: H W M
authors.initials: HW
authors.lastname: Steinbusch
authors.affiliation: 1] Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Wuerzburg, Wuerzburg, Germany [2] Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands.
authors.forename: K P
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: 1] Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Center of Mental Health, Department of Psychiatry, University of Wuerzburg, Wuerzburg, Germany [2] Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands.
authors.forename: D L
authors.initials: DL
authors.lastname: Van den Hove
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006624:Hippocampus; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics*
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins