Background Epigenetic modifications, including DNA methylation, play an important role in gene silencing and genome stability. Consequently, epigenetic dysregulation can cause several diseases, such as cancer, obesity, diabetes, autism, and imprinting disorders. Results We validate three methods for the generation of epigenome-edited mice using the dCas9-SunTag and single-chain variable fragment-TET1 catalytic domain. We generate model mice for Silver-Russell syndrome (SRS), an imprinting disorder, by target-specific DNA demethylation in the H19 differentially methylated region. Like SRS patients, these mice show H19 upregulation and Igf2 downregulation, leading to severe intrauterine and postnatal growth retardation. Conclusion This is the first report of an imprinting disease model animal generated by targeted demethylation of specific loci of the epigenome in fertilized eggs. Epigenome-edited animals are also useful for exploring the causative epimutations in epigenetic diseases.

中文翻译：

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通过表观基因组靶向去甲基化成功产生表观遗传疾病模型小鼠


背景 表观遗传修饰，包括 DNA 甲基化，在基因沉默和基因组稳定性中发挥着重要作用。因此，表观遗传失调可导致多种疾病，如癌症、肥胖、糖尿病、自闭症和印记障碍。结果我们验证了使用 dCas9-SunTag 和单链可变片段-TET1 催化结构域生成表观基因组编辑小鼠的三种方法。我们通过 H19 差异甲基化区域中的目标特异性 DNA 去甲基化来生成 Silver-Russell 综合征 (SRS)（一种印迹疾病）的模型小鼠。与 SRS 患者一样，这些小鼠表现出 H19 上调和 Igf2 下调，导致严重的宫内和产后生长迟缓。结论 这是通过受精卵表观基因组特定位点定向去甲基化产生的印记疾病模型动物的首次报道。表观基因组编辑的动物也可用于探索表观遗传疾病的致病表观突变。