A multistep epigenetic switch enables the stable inheritance of DNA methylation states
A multistep epigenetic switch enables the stable inheritance of DNA methylation states
复制标题
DOI：
10.1038/ng1956
复制
发表时间：
2007-02-01
期刊：
影响因子：
30.8
通讯作者：
van Oudenaarden, Alexander
中科院分区：
文献类型：
--
作者：
Lim, Han N.;van Oudenaarden, Alexander
在许多原核生物和真核生物中，顺式调控序列的 DNA 甲基化决定基因表达的开启或关闭。细菌发病机制、癌症和发育途径需要这些表达状态的稳定遗传(1,2)。在这里，我们使用大肠杆菌中的 agn43 基因作为模型系统，描述了控制这些状态稳定性的因素。该系统的系统性破坏表明，功能开关需要存在几个很少占用的中间状态，以分隔“开”和“关”状态。离开开启和关闭状态的细胞会进入不同的中间状态，其中存在强烈的偏置，驱动细胞回到原始状态。因此，中间状态充当防止来回切换的缓冲器。这种产生多个状态的机制是反馈调节的替代方案(3-5)，其一般原理应该适用于其他表观遗传开关的分析和合成电路的设计。
In many prokaryotes and eukaryotes, DNA methylation at cis-regulatory sequences determines whether gene expression is on or off. Stable inheritance of these expression states is required in bacterial pathogenesis, cancer and developmental pathways(1,2). Here we delineate the factors that control the stability of these states by using the agn43 gene in Escherichia coli as a model system. Systematic disruption of this system shows that a functional switch requires the presence of several, rarely occupied, intermediate states that separate the 'on' and 'off' states. Cells that leave the on and off state enter different intermediate states, where there is a strong bias that drives cells back to their original state. The intermediate states therefore act as buffers that prevent back and forth switching. This mechanism of generating multiple states is an alternative to feedback regulation(3-5), and its general principle should be applicable to the analysis of other epigenetic switches and the design of synthetic circuits.