Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice.
Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice.
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DOI：
10.1038/tp.2014.107
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发表时间：
2014-10-21
影响因子：
6.8
通讯作者：
Van den Hove DL
中科院分区：
文献类型：
--
作者：
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
5-羟色胺转运体基因(5-HTT/SLC6A4)连锁的多态区域被认为在早期应激暴露对精神病理的影响中具有调制作用，使得低表达短(S)突变的携带者在以后的生活中更容易受到环境逆境的影响。这种基因-环境相互作用的潜在分子机制尚不清楚，但包括差异DNA甲基化在内的表观遗传调控被认为具有关键作用。最近，我们在5-HTT缺陷小鼠的产前应激(PS)中使用了母体束缚应激范式，结果表明，这种应激对雌性5-HTT+/−子代的行为和基因表达的影响尤为显著。在这里，我们研究了这些效应在多大程度上是由DNA的差异甲基化介导的。为此，我们在Affymetrix基因芯片小鼠启动子1.0 R阵列上使用甲基化DNA免疫沉淀法进行了全基因组海马区DNA甲基化筛查。使用之前评估过的相同小鼠的海马区DNA，使我们能够将基因特异的DNA甲基化、mRNA表达和行为联系起来。我们发现，5-Htt基因、PS及其相互作用对许多基因的DNA甲基化特征有不同的影响，其中一部分与相应转录本的表达谱有重叠。例如，编码髓鞘碱性蛋白(MBP)的基因中的一个差异甲基化区域与其表达以5-Htt、PS-和5-Htt×PS依赖的方式相关。随后对该MBP基因座的精细定位将两个特定CpG位点的甲基化状态与MBP的表达和焦虑相关行为联系起来。总之，孕期应激雌性5-Htt+/−小鼠的海马DNA甲基化模式和表达谱表明，不同的分子机制，其中一些是启动子甲基化依赖的，有助于5-Htt基因、PS暴露及其相互作用的行为效应。
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.
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