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

K.G. Schraut, S.B. Jakob, M.T. Weidner, A.G. Schmitt, C.J. Scholz, T. Strekalova, N. El Hajj, L.M. Eijssen, K. Domschke, A. Reif, T. Haaf, G. Ortega, H.W. Steinbusch, K.P. Lesch, D.L. Van den Hove

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

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 x 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.
Original languageEnglish
Article numbere473
Number of pages10
JournalTranslational Psychiatry
Volume4
DOIs
Publication statusPublished - Oct 2014

Keywords

  • MYELIN BASIC-PROTEIN
  • CONVERGENT FUNCTIONAL GENOMICS
  • BIPOLAR AFFECTIVE-DISORDER
  • V PHOSPHOLIPASE A(2)
  • ELEVATED PLUS-MAZE
  • MAJOR DENSE LINE
  • GENE-EXPRESSION
  • HIPPOCAMPAL MYELINATION
  • PSYCHIATRIC-DISORDERS
  • SEROTONIN TRANSPORTER

Cite this

Schraut, K. G., Jakob, S. B., Weidner, M. T., Schmitt, A. G., Scholz, C. J., Strekalova, T., ... Van den Hove, D. L. (2014). Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice. Translational Psychiatry, 4, [e473]. https://doi.org/10.1038/tp.2014.107
Schraut, K.G. ; Jakob, S.B. ; Weidner, M.T. ; Schmitt, A.G. ; Scholz, C.J. ; Strekalova, T. ; El Hajj, N. ; Eijssen, L.M. ; Domschke, K. ; Reif, A. ; Haaf, T. ; Ortega, G. ; Steinbusch, H.W. ; Lesch, K.P. ; Van den Hove, D.L. / Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice. In: Translational Psychiatry. 2014 ; Vol. 4.
@article{0e290da475b346839dff73a069d325a6,
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 x 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.",
keywords = "MYELIN BASIC-PROTEIN, CONVERGENT FUNCTIONAL GENOMICS, BIPOLAR AFFECTIVE-DISORDER, V PHOSPHOLIPASE A(2), ELEVATED PLUS-MAZE, MAJOR DENSE LINE, GENE-EXPRESSION, HIPPOCAMPAL MYELINATION, PSYCHIATRIC-DISORDERS, SEROTONIN TRANSPORTER",
author = "K.G. Schraut and S.B. Jakob and M.T. Weidner and A.G. Schmitt and C.J. Scholz and T. Strekalova and {El Hajj}, N. and L.M. Eijssen and K. Domschke and A. Reif and T. Haaf and G. Ortega and H.W. Steinbusch and K.P. Lesch and {Van den Hove}, D.L.",
year = "2014",
month = "10",
doi = "10.1038/tp.2014.107",
language = "English",
volume = "4",
journal = "Translational Psychiatry",
issn = "2158-3188",
publisher = "Nature Publishing Group",

}

Schraut, KG, Jakob, SB, Weidner, MT, Schmitt, AG, Scholz, CJ, Strekalova, T, El Hajj, N, Eijssen, LM, Domschke, K, Reif, A, Haaf, T, Ortega, G, Steinbusch, HW, Lesch, KP & Van den Hove, DL 2014, 'Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice', Translational Psychiatry, vol. 4, e473. https://doi.org/10.1038/tp.2014.107

Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice. / Schraut, K.G.; Jakob, S.B.; Weidner, M.T.; Schmitt, A.G.; Scholz, C.J.; Strekalova, T.; El Hajj, N.; Eijssen, L.M.; Domschke, K.; Reif, A.; Haaf, T.; Ortega, G.; Steinbusch, H.W.; Lesch, K.P.; Van den Hove, D.L.

In: Translational Psychiatry, Vol. 4, e473, 10.2014.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice

AU - Schraut, K.G.

AU - Jakob, S.B.

AU - Weidner, M.T.

AU - Schmitt, A.G.

AU - Scholz, C.J.

AU - Strekalova, T.

AU - El Hajj, N.

AU - Eijssen, L.M.

AU - Domschke, K.

AU - Reif, A.

AU - Haaf, T.

AU - Ortega, G.

AU - Steinbusch, H.W.

AU - Lesch, K.P.

AU - Van den Hove, D.L.

PY - 2014/10

Y1 - 2014/10

N2 - 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 x 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.

AB - 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 x 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.

KW - MYELIN BASIC-PROTEIN

KW - CONVERGENT FUNCTIONAL GENOMICS

KW - BIPOLAR AFFECTIVE-DISORDER

KW - V PHOSPHOLIPASE A(2)

KW - ELEVATED PLUS-MAZE

KW - MAJOR DENSE LINE

KW - GENE-EXPRESSION

KW - HIPPOCAMPAL MYELINATION

KW - PSYCHIATRIC-DISORDERS

KW - SEROTONIN TRANSPORTER

U2 - 10.1038/tp.2014.107

DO - 10.1038/tp.2014.107

M3 - Article

VL - 4

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

M1 - e473

ER -