Engineering Epigenetic Regulation Using Synthetic Read-Write Modules
Engineering Epigenetic Regulation Using Synthetic Read-Write Modules
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DOI：
10.1016/j.cell.2018.11.002
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发表时间：
2019-01-10
期刊：
影响因子：
64.5
通讯作者：
Khalil，Ahmad S.
中科院分区：
文献类型：
--
作者：
Park，Minhee;Patel，Nikit;Khalil，Ahmad S.
对DNA和组蛋白的化学修饰涉及细胞分化和发育的表观遗传程序。涉及染色质标记的分子书写者和阅读者的调控网络被认为控制这些程序。在这一共同原则的指导下，我们使用N6-甲基腺嘌呤（m6 A），一种在后生动物表观基因组中不常见的DNA修饰，在哺乳动物细胞中建立了一个正交的表观遗传调控系统。我们的系统利用合成因子，写入和读取m6 A，从而招募转录调节因子来控制报告基因座。受染色质扩散和表观遗传模型的启发，我们使用我们的系统和数学模型来构建诱导m6 A依赖性转录状态的调控回路，促进其空间传播，并保持状态的表观遗传记忆。这些最小的电路能够重新编程表观遗传功能，在概念上验证“读写”架构。这项工作提供了一个工具包，用于研究表观遗传调控模型和编码细胞中表观遗传信息的附加层。
Chemical modifications to DNA and histone proteins are involved in epigenetic programs underlying cellular differentiation and development. Regulatory networks involving molecular writers and readers of chromatin marks are thought to control these programs. Guided by this common principle, we established an orthogonal epigenetic regulatory system in mammalian cells using N6-methyladenine (m6A), a DNA modification not commonly found in metazoan epigenomes. Our system utilizes synthetic factors that write and read m6A and consequently recruit transcriptional regulators to control reporter loci. Inspired by models of chromatin spreading and epigenetic inheritance, we used our system and mathematical models to construct regulatory circuits that induce m6A-dependent transcriptional states, promote their spatial propagation, and maintain epigenetic memory of the states. These minimal circuits were able to program epigenetic functionsde novo, conceptually validating "read-write" architectures. This work provides a toolkit for investigating models of epigenetic regulation and encoding additional layers of epigenetic information in cells.