Maurano Matthew T, Wang Hao, John Sam, Shafer Anthony, Canfield Theresa, Lee Kristen, Stamatoyannopoulos John A
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Cell Rep. 2015 Aug 18;12(7):1184-95. doi: 10.1016/j.celrep.2015.07.024. Epub 2015 Aug 6.
Although DNA methylation is commonly invoked as a mechanism for transcriptional repression, the extent to which it actively silences transcription factor (TF) occupancy sites in vivo is unknown. To study the role of DNA methylation in the active modulation of TF binding, we quantified the effect of DNA methylation depletion on the genomic occupancy patterns of CTCF, an abundant TF with known methylation sensitivity that is capable of autonomous binding to its target sites in chromatin. Here, we show that the vast majority (>98.5%) of the tens of thousands of unoccupied, methylated CTCF recognition sequences remain unbound upon abrogation of DNA methylation. The small fraction of sites that show methylation-dependent binding in vivo are in turn characterized by highly variable CTCF occupancy across cell types. Our results suggest that DNA methylation is not a primary groundskeeper of genomic TF landscapes, but rather a specialized mechanism for stabilizing intrinsically labile sites.
尽管DNA甲基化通常被认为是一种转录抑制机制，但在体内它对转录因子（TF）占据位点进行主动沉默的程度尚不清楚。为了研究DNA甲基化在TF结合的主动调节中的作用，我们量化了DNA甲基化缺失对CTCF基因组占据模式的影响，CTCF是一种丰富的TF，具有已知的甲基化敏感性，能够自主结合染色质中的靶位点。在这里，我们表明，在消除DNA甲基化后，数以万计未被占据的甲基化CTCF识别序列中，绝大多数（>98.5%）仍然未被结合。在体内表现出甲基化依赖性结合的一小部分位点，其特征是在不同细胞类型中CTCF的占据高度可变。我们的结果表明，DNA甲基化不是基因组TF景观的主要守护者，而是一种稳定内在不稳定位点的特殊机制。
