Dobosy Joseph R, Fu Vivian X, Desotelle Joshua A, Srinivasan Rajini, Kenowski Michelle L, Almassi Nima, Weindruch Richard, Svaren John, Jarrard David F
Environmental and Molecular Toxicology, University of Wisconsin, Madison, Wisconsin 53792, USA.
Prostate. 2008 Aug 1;68(11):1187-95. doi: 10.1002/pros.20782.
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.
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.
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.
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.
叶酸和甲基缺乏与前列腺癌易感性有关，然而这些观察结果背后的机制尚未完全了解。基因组中包含印记基因胰岛素样生长因子2（Igf2）和H19的区域，这两个基因都具有致癌功能，可能对环境影响特别敏感。
为了确定甲基缺乏饮食是否会影响Igf2 - H19基因座的表观遗传控制，我们将在印记Igf2 - H19基因座存在多态性的C57BL / 6小鼠置于胆碱和蛋氨酸缺乏（CMD）饮食中。我们研究了该基因座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Igf2和H19的表达均显著增加。这些表达变化在较短时间暴露于CMD饮食后是可逆的。染色质免疫沉淀（ChIP）显示H19启动子以及Igf2 P2和P3启动子内的抑制性组蛋白修饰（二甲基 - H3K9）显著减少。这些启动子内的DNA甲基化没有改变。未观察到Igf2或H19印记的显著变化。
这些发现突出了表观基因组在易发生肿瘤变化的上皮器官中的可塑性。它们进一步表明，在这个基因座上，染色质修饰比DNA甲基化更容易受到甲基缺乏饮食的影响。
