Investigation into the role of the germline epigenome in the transmission of glucocorticoid-programmed effects across generations.
Investigation into the role of the germline epigenome in the transmission of glucocorticoid-programmed effects across generations.
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DOI：
10.1186/s13059-018-1422-4
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发表时间：
2018-04-10
期刊：
影响因子：
12.3
通讯作者：
Drake AJ
中科院分区：
文献类型：
--
作者：
Cartier J;Smith T;Thomson JP;Rose CM;Khulan B;Heger A;Meehan RR;Drake AJ
早期生活暴露于不利环境会影响后代的心血管和代谢系统。这些程序性效应是通过男性和女性线条传递给第二代的，这表明种系传播。我们先前已经表明，大鼠中合成糖皮质激素地塞米松（DEX）的产前过度暴露会减少第一代（F1）的出生体重，这是一种传播到第二代（F2）的表型，尤其是通过男性线。我们假设DEX暴露会影响发展的生殖细胞，从而导致雄性种系中DNA甲基化，组蛋白标记和/或小RNA的可传播改变。
我们使用甲基化的DNA免疫沉淀测序，小的RNA测序和H3K4ME3，H3K4ME1，H3K4ME1，H3K27，我们使用F1 Sprague Dawley大鼠的精子中的表观遗传标记，表达生殖细胞特异性GFP转基因或母亲的媒介物治疗，使用甲基化的DNA免疫沉淀测序和染色质蛋白免疫测序。尽管对出生体重的影响通过雄性线传播到F2生成，但在DNA甲基化，组蛋白的修饰或小小的RNA之间没有差异，从细胞和精子之间发现了暴露于DEX的动物和对照组的精子。
尽管表型传播到第二代，但我们无法检测到精子中的DNA甲基化，常见组蛋白修饰或小的RNA谱的特定变化。 DEX暴露与更可变的5MC水平相关，尤其是在非促进剂基因座。尽管这可能是有助于观察到的表型的一种机制，但其他种系表观遗传修饰或非观测机制可能是导致该模型中各代程序效应的传播。
本文的在线版本（10.1186/S13059-018-1422-4）包含补充材料，可供授权用户使用。
Early life exposure to adverse environments affects cardiovascular and metabolic systems in the offspring. These programmed effects are transmissible to a second generation through both male and female lines, suggesting germline transmission. We have previously shown that prenatal overexposure to the synthetic glucocorticoid dexamethasone (Dex) in rats reduces birth weight in the first generation (F1), a phenotype which is transmitted to a second generation (F2), particularly through the male line. We hypothesize that Dex exposure affects developing germ cells, resulting in transmissible alterations in DNA methylation, histone marks and/or small RNA in the male germline. We profile epigenetic marks in sperm from F1 Sprague Dawley rats expressing a germ cell-specific GFP transgene following Dex or vehicle treatment of the mothers, using methylated DNA immunoprecipitation sequencing, small RNA sequencing and chromatin immunoprecipitation sequencing for H3K4me3, H3K4me1, H3K27me3 and H3K9me3. Although effects on birth weight are transmitted to the F2 generation through the male line, no differences in DNA methylation, histone modifications or small RNA were detected between germ cells and sperm from Dex-exposed animals and controls. Although the phenotype is transmitted to a second generation, we are unable to detect specific changes in DNA methylation, common histone modifications or small RNA profiles in sperm. Dex exposure is associated with more variable 5mC levels, particularly at non-promoter loci. Although this could be one mechanism contributing to the observed phenotype, other germline epigenetic modifications or non-epigenetic mechanisms may be responsible for the transmission of programmed effects across generations in this model. The online version of this article (10.1186/s13059-018-1422-4) contains supplementary material, which is available to authorized users.
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