Métivier Raphaël, Gallais Rozenn, Tiffoche Christophe, Le Péron Christine, Jurkowska Renata Z, Carmouche Richard P, Ibberson David, Barath Peter, Demay Florence, Reid George, Benes Vladimir, Jeltsch Albert, Gannon Frank, Salbert Gilles
Université de Rennes I, CNRS, UMR 6026 Equipe SPARTE, IFR 140 GFAS, Campus de Beaulieu, 35042 Rennes cedex, France.
Nature. 2008 Mar 6;452(7183):45-50. doi: 10.1038/nature06544.
Processes that regulate gene transcription are directly under the influence of the genome organization. The epigenome contains additional information that is not brought by DNA sequence, and generates spatial and functional constraints that complement genetic instructions. DNA methylation on CpGs constitutes an epigenetic mark generally correlated with transcriptionally silent condensed chromatin. Replication of methylation patterns by DNA methyltransferases maintains genome stability through cell division. Here we present evidence of an unanticipated dynamic role for DNA methylation in gene regulation in human cells. Periodic, strand-specific methylation/demethylation occurs during transcriptional cycling of the pS2/TFF1 gene promoter on activation by oestrogens. DNA methyltransferases exhibit dual actions during these cycles, being involved in CpG methylation and active demethylation of 5mCpGs through deamination. Inhibition of this process precludes demethylation of the pS2 gene promoter and its subsequent transcriptional activation. Cyclical changes in the methylation status of promoter CpGs may thus represent a critical event in transcriptional achievement.
调控基因转录的过程直接受基因组组织的影响。表观基因组包含并非由DNA序列带来的额外信息，并产生补充遗传指令的空间和功能限制。CpG位点上的DNA甲基化构成一种表观遗传标记，通常与转录沉默的浓缩染色质相关。DNA甲基转移酶对甲基化模式的复制通过细胞分裂维持基因组稳定性。在此，我们展示了DNA甲基化在人类细胞基因调控中具有意外的动态作用的证据。在雌激素激活后，pS2/TFF1基因启动子的转录循环过程中会发生周期性的、链特异性的甲基化/去甲基化。DNA甲基转移酶在这些循环中表现出双重作用，参与CpG甲基化以及通过脱氨作用对5mCpGs进行主动去甲基化。抑制这一过程会阻止pS2基因启动子的去甲基化及其随后的转录激活。因此，启动子CpG甲基化状态的周期性变化可能代表转录完成中的一个关键事件。
