Epigenetic instability at imprinting control regions in a KrasG12D-induced T-cell neoplasm
Epigenetic instability at imprinting control regions in a KrasG12D-induced T-cell neoplasm
复制标题
DOI：
10.1080/15592294.2015.1110672
复制
发表时间：
2015-12-02
期刊：
影响因子：
3.7
通讯作者：
Kim, Joomyeong
中科院分区：
文献类型：
--
作者：
Bretz, Corey L.;Langohr, Ingeborg M.;Kim, Joomyeong
尽管在多种肿瘤性疾病中已经报道了印迹结构域内的异常DNA甲基化，但在致癌作用的背景下，它仍然在很大程度上没有被表征。在这项研究中，我们诱导T细胞淋巴瘤的小鼠采用育种计划，涉及小鼠品系，LSL-Kras（G12 D）和MMTV-Cre。然后，我们系统地调查印迹结构域的DNA甲基化的变化，在肿瘤进展过程中使用相结合的亚硫酸氢盐限制性分析和NGS为基础的亚硫酸氢盐测序。我们在Dlk 1、Peg 10、Peg 3、Grb 10和Gnas结构域的印迹控制区（ICR）检测到高甲基化或低甲基化。这些DNA甲基化的变化在ICR是更普遍和一致的比那些在众所周知的肿瘤抑制基因，如Mgmt，Fhit，和Mlh 1的启动子区域观察到的。因此，在这些印迹结构域观察到的变化是影响DNA甲基化设置的孤立事件的结果。在印迹结构域内，DNA甲基化变化往往限于ICR，因为附近的体细胞差异甲基化区域和启动子区域没有变化。此外，详细的分析显示，ICR内的小顺式调控元件往往对DNA甲基化变化具有抗性，这表明未知的反式因子具有潜在的保护作用。总体而言，这项研究表明，在ICR的DNA甲基化变化是动态的，在致癌过程中，并主张在ICR异常DNA甲基化的检测可以作为一种生物标志物，以加强诊断程序。
Although aberrant DNA methylation within imprinted domains has been reported in a variety of neoplastic diseases, it remains largely uncharacterized in the context of carcinogenesis. In this study, we induced T-cell lymphoma in mice by employing a breeding scheme involving mouse strains, LSL-Kras(G12D) and MMTV-Cre. We then systematically surveyed imprinted domains for DNA methylation changes during tumor progression using combined bisulfite restriction analysis and NGS-based bisulfite sequencing. We detected hyper- or hypo-methylation at the imprinting control regions (ICRs) of the Dlk1, Peg10, Peg3, Grb10, and Gnas domains. These DNA methylation changes at ICRs were more prevalent and consistent than those observed at the promoter regions of well-known tumor suppressors, such as Mgmt, Fhit, and Mlh1. Thus, the changes observed at these imprinted domains are the outcome of isolated incidents affecting DNA methylation settings. Within imprinted domains, DNA methylation changes tend to be restricted to ICRs as nearby somatic differentially methylated regions and promoter regions experience no change. Furthermore, detailed analyses revealed that small cis-regulatory elements within ICRs tend to be resistant to DNA methylation changes, suggesting potential protection by unknown trans-factors. Overall, this study demonstrates that DNA methylation changes at ICRs are dynamic during carcinogenesis and advocates that detection of aberrant DNA methylation at ICRs may serve as a biomarker to enhance diagnostic procedures.