Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues
Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues
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DOI：
10.1038/ng.2442
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发表时间：
2012-11-01
期刊：
影响因子：
30.8
通讯作者：
Tanay, Amos
中科院分区：
文献类型：
--
作者：
Landan, Gilad;Cohen, Netta Mendelson;Tanay, Amos
正常细胞和癌细胞中的 DNA 甲基化已得到全面分析，但形成、维持和重新编程差异甲基化区域的动态仍然是个谜。在这里，我们表明来自个体体细胞组织的细胞群内的甲基化模式是异质性和多态性的。利用永生化成纤维细胞超过 300 代的体外进化，我们追踪了平均出现显着差异甲基化的区域的多态甲基化动态。数据表明，群体平均甲基化的变化是通过随机过程发生的，该过程产生一系列局部且不相关的甲基化畸变。尽管该过程具有随机性，但平均而言，在失去或获得对甲基化积累的抵抗力的基因座上会出现近乎确定性的表观遗传重塑。对甲基化积累的敏感性的变化与组蛋白修饰和 CTCF 占据的变化相关。因此，表征细胞群内的表观基因组多态性对于了解正常细胞和癌细胞的甲基化动态至关重要。
DNA methylation has been comprehensively profiled in normal and cancer cells, but the dynamics that form, maintain and reprogram differentially methylated regions remain enigmatic. Here, 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 modification and CTCF occupancy. Characterizing epigenomic polymorphism within cell populations is therefore critical to understanding methylation dynamics in normal and cancer cells.