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 functions de 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.

中文翻译：

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使用综合读写模块进行工程表观遗传调控。

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。据认为，涉及染色质标记的分子作者和读者的监管网络可以控制这些程序。遵循这一共同原则，我们使用N6-甲基腺嘌呤（m6A）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正交的表观遗传调控系统。我们的系统利用合成因子来读写m6A，并因此募集转录调节因子来控制报道基因座。受染色质扩散和表观遗传遗传模型的启发，我们使用系统和数学模型构建了调控电路，该电路诱导了m6A依赖的转录状态，促进了它们的空间传播，并保持状态的表观记忆。这些最小的电路能够重新编程表观遗传函数，从概念上验证了“读写”体系结构。这项工作为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提供了一个工具包。