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.

Positive and balancing selection onSLC18A1gene associated with psychiatric disorders and human-unique personality traits

“…Schraut et al. () identified Fat1 as a gene whose methylation level is affected by interaction with the 5‐Htt genotype (wild‐type: +/+ and heterozygous: +/−) and prenatal stress exposure in mice. They have also found that prenatal stress exposure increases the methylation level of Clstn2 and decreases its expression level.…”

Failure to upregulate Agrp and Orexin in response to activity based anorexia in weight loss vulnerable rats characterized by passive stress coping and prenatal stress experience

“…DNAm modulates gene transcription without altering the DNA sequence itself (Auclair and Weber, 2012) and prenatal stress has been shown to alter DNAm (Boersma et al, 2014b; Palacios-Garcia et al, 2015; Paternain et al, 2012; Schraut et al, 2014). We considered whether PNS exposure altered DNAm of the Agrp gene.…”

Stress In Utero: Prenatal Programming of Brain Plasticity and Cognition

“…The 5HTT 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. It was found that 5-HTT genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes (110). A number of studies searched for epigenetic bio-markers of PS in the placenta.…”