DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease
DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease
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DOI：
10.1073/pnas.1703087114
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发表时间：
2017-09-05
影响因子：
11.1
通讯作者：
Tufarelli, Cristina
中科院分区：
文献类型：
--
作者：
Jeziorska, Danuta M.;Murray, Robert J. S.;Tufarelli, Cristina
人类基因组包含大约3万个CpG岛（cgi）。虽然与启动子相关的cgi几乎总是保持未甲基化，但位于基因体内的9000个类似的cgi中的许多在发育和分化过程中被甲基化。在恶性肿瘤中，启动子和基因内基因也可能由于基因组后位而异常甲基化。在这些情况下，一些cgi发生甲基化而另一些在同一细胞中保持未甲基化的表观遗传机制尚不清楚。通过对特定位点的分析和全基因组分析，研究人员发现，DNA甲基转移酶3B （DNMT3B）介导的许多自然发生的基因内基因的DNA甲基化需要与特定染色质修饰相关的转录在基因序列中运行。重要的是，我们还表明，基因内cgi的一个亚群对转录介导的甲基化过程不敏感，这与它们在体内启动转录的个体内在能力有关。我们提出了一个关于转录如何作为正常发育和分化以及人类疾病中CGI甲基化模式的主要决定因素的一般模型。
The human genome contains similar to 30,000 CpG islands (CGIs). While CGIs associated with promoters nearly always remain unmethylated, many of the similar to 9,000 CGIs lying within gene bodies become methylated during development and differentiation. Both promoter and intragenic CGIs may also become abnormally methylated as a result of genome rear-rangements and in malignancy. The epigenetic mechanisms by which some CGIs become methylated but others, in the same cell, remain unmethylated in these situations are poorly understood. Analyzing specific loci and using a genome-wide analysis, we show that transcription running across CGIs, associated with specific chromatin modifications, is required for DNA methyltransferase 3B (DNMT3B)-mediated DNA methylation of many naturally occurring intragenic CGIs. Importantly, we also show that a subgroup of intragenic CGIs is not sensitive to this process of transcription -mediated methylation and that this correlates with their individual intrinsic capacity to initiate transcription in vivo. We propose a general model of how transcription could ad as a primary determinant of the patterns of CGI methylation in normal development and differentiation, and in human disease.