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Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice

Please always quote using this URN: urn:nbn:de:bvb:20-opus-119199
  • 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 maternalThe 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.show moreshow less

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Metadaten
Author: K. G. Schraut, S. B. Jakob, M. T. Weidner, A. G. Schmitt, C. J. Scholz, T. Strekalova, N. El Hajj, L. M. T. Eijssen, K. Domschke, A. Reif, T. Haaf, G. Ortega, H. W. M. Steinbusch, K. P. Lesch, D. L. Van den Hove
URN:urn:nbn:de:bvb:20-opus-119199
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Humangenetik
Medizinische Fakultät / Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Medizinische Fakultät / Lehrstuhl für Molekulare Psychiatrie
Language:English
Parent Title (English):Translational Psychiatry
Year of Completion:2014
Volume:4
Pagenumber:e473
Source:Translational Psychiatry (2014) 4, e473; doi:10.1038/tp.2014.107
DOI:https://doi.org/10.1038/tp.2014.107
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25335169
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 611 Menschliche Anatomie, Zytologie, Histologie
Tag:DNA; mice
Release Date:2015/10/20
EU-Project number / Contract (GA) number:602805
OpenAIRE:OpenAIRE
Licence (German):License LogoCC BY-NC-SA: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Weitergabe unter gleichen Bedingungen