A methyl-deficient diet modifies histone methylation and alters Igf2 and H19 repression in the prostate
A methyl-deficient diet modifies histone methylation and alters Igf2 and H19 repression in the prostate
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DOI：
10.1002/pros.20782
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发表时间：
2008-08-01
期刊：
影响因子：
2.8
通讯作者：
Jarrard, David F.
中科院分区：
文献类型：
--
作者：
Dobosy, Joseph R.;Fu, Vivian X.;Jarrard, David F.
背景叶酸和甲基缺乏与前列腺癌易感性有关，但这些观察结果的机制尚未完全了解。基因组区域包含印记基因胰岛素样生长因子2（Igf 2）和H19，这两个基因都显示致癌功能，可能对环境影响特别敏感。为了确定甲基缺乏饮食是否影响Igf 2-H19基因座的表观遗传控制，我们将含有印迹Igf 2-H19基因座多态性的C57 BL/6小鼠置于胆碱和甲硫氨酸缺乏（CMD）饮食中。我们询问了这个位点在前列腺组织中的表达和表观遗传变化。与对照组相比，CMD前列腺组织中Igf 2和H19表达均显著增加。这些表达变化是可逆的，暴露于CMD饮食的时间较短。染色质免疫沉淀（ChIP）显示H19启动子以及Igf 2 P2和P3启动子内的抑制性组蛋白修饰（二甲基-H3 K9）显著减少。这些启动子内的DNA甲基化没有改变。Igf 2或H19印迹无显著变化。这些发现突出了易受肿瘤变化影响的上皮器官中表观基因组的可塑性。他们进一步表明，染色质修饰比该位点的DNA甲基化更容易受到甲基缺乏饮食的影响。
BACKGROUND. Folate and methyl-group deficiency has been linked to prostate cancer susceptibility, yet the mechanisms underlying these observations are incompletely understood. The region of the genome containing the imprinted genes insulin-like growth factor 2 (Igf2) and H19, both of which display oncogenic functions, may be particularly sensitive to environmental influences.METHODS. To determine whether a methyl-deficient diet impacts epigenetic controls at the Igf2 -H19 locus, we placed C57BL/6 mice containing a polymorphism at the imprinted Igf2-H19 locus on a choline and methionine deficient (CMD) diet. We interrogated this locus for expression and epigenetic changes in prostate tissues.RESULTS. A significant increase in both Igf2 and H19 expression was found in CMD prostate tissues compared to controls. These expression changes were reversible with shorter exposure to the CMD diet. Chromatin immunoprecipitation (ChIP) revealed significant decreases in repressive histone modifications (dimethyl-H3K9) within the H19 promoter, as well as Igf2 P2 and P3 promoters. DNA methylation within these promoters was not altered. No significant change in Igf2 or H19 imprinting was observed.CONCLUSIONS. These findings highlight the plasticity of the epigenome in an epithelial organ vulnerable to neoplastic change. They further suggest that chromatin modifications are more susceptible to methyl-deficient diets than DNA methylation at this locus.