Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues (Gene Expression data)

DNA methylation has been comprehensively profiled in normal and cancer cells, but the dynamics that form, maintain and reprogram differentially methylated regions remain enigmatic. We show that methylation patterns within populations of cells from individual somatic tissues are heterogeneous and polymorphic. Using in vitro evolution of immortalized fibroblasts for over 300 generations, we track the dynamics of polymorphic methylation at regions developing significant differential methylation on average. The data indicate that changes in population-averaged methylation occur through a stochastic process that generates a stream of local and uncorrelated methylation aberrations. Despite the stochastic nature of the process, nearly deterministic epigenetic remodeling emerges on average at loci that lose or gain resistance to methylation accumulation. Changes in the susceptibility to methylation accumulation are correlated with changes in histone modifications and CTCF occupancy. Characterizing epigenomic polymorphism within cell populations is therefore critical for understanding methylation dynamics in normal and cancer cells. Gene expression profiled in duplicate throughout the microevolutionary timecourse using Affymetrix Gene 1.0 ST arrays.

DNA甲基化（DNA methylation）已在正常细胞与癌细胞中得到全面表征，但形成、维持并重编程差异甲基化区域（differentially methylated regions）的动态调控机制仍未阐明。本研究证实，来自单个体细胞组织（somatic tissues）的细胞群体内的甲基化模式存在异质性与多态性。通过对永生化成纤维细胞（immortalized fibroblasts）进行超过300代的体外进化培养，我们追踪了平均水平上出现显著差异甲基化的区域内，多态性甲基化的动态变化过程。研究数据表明，群体平均甲基化水平的改变通过一种随机过程（stochastic process）实现，该过程会产生一系列局部且互不关联的甲基化异常（methylation aberrations）事件。尽管该过程具有随机性，但在那些获得或丧失甲基化积累抗性的基因座（loci）上，平均层面上会呈现出近乎确定性的表观遗传重塑（epigenetic remodeling）。甲基化积累易感性的改变与组蛋白修饰（histone modifications）及CTCF（CCCTC结合因子）结合占据情况的变化存在相关性。因此，对细胞群体内的表观基因组多态性（epigenomic polymorphism）进行表征，对于阐明正常细胞与癌细胞中的甲基化动态调控机制至关重要。本研究使用Affymetrix Gene 1.0 ST芯片，对整个微进化时间进程中的基因表达进行了两次生物学重复检测。