Reprogramming oncogene levels through gene body hypermethylation in RTK-driven cancer. Mus musculus

While promoter epigenetic modifications have been linked to tumor suppressor silencing in cancers, modifications in gene body regions has been largely neglected. Using a genetic setting in which subtle enhanced levels of non-oncogenic receptor tyrosine kinases (RTKs) become progressively pathological, we show that reprogrammed CpG island (CGI) methylation locks cells into tumorigenicity. By focusing on gene bodies, we found an enrichment of hypermethylated CGI similar to that reported in cancer patients. Gene body CGI hypermethylation correlates with decreased H3K27me3 modification and enhanced transcription for a proportion of genes, which act as oncogenes in cancer cells. Collectively, our results illustrate that tumorigenesis is ensured by an increase dosage of a set of oncogenes through an epigenetic reprogramming involving gene body CGI hypermethylation. Overall design: Genomic DNA from dissected Alb-R26Met tumors (n=10) and control livers (n=3) was used to analyze the DNA methylation profile

尽管启动子表观遗传修饰已与癌症中的抑癌基因沉默建立关联，但基因本体区域的表观遗传修饰在很大程度上仍被忽视。本研究利用一种遗传模型体系，在该体系中，非致癌性受体酪氨酸激酶（receptor tyrosine kinases, RTKs）的轻度上调表达水平逐渐发展为致病状态，结果显示重编程的CpG岛（CGI）甲基化会将细胞锁定于致瘤状态。通过聚焦基因本体区域，我们发现了与癌症患者中报道的高甲基化CGI富集特征相似的现象。基因本体CGI高甲基化与部分基因的H3K27me3修饰水平降低以及转录激活增强相关，这类基因在癌细胞中发挥致癌基因的功能。综上，本研究结果表明，肿瘤发生可通过涉及基因本体CGI高甲基化的表观重编程，使一组致癌基因的表达剂量增加得以实现。实验整体设计：提取自10例Alb-R26Met肿瘤组织（n=10）与3例对照肝脏组织（n=3）的基因组DNA，被用于分析DNA甲基化谱。