Epigenetic inheritance of gene expression states enables a single genome to maintain distinct cellular identities. How histone modifications contribute to this process remains unclear. Using global chromatin perturbations and local, time-controlled modulation of transcription, we establish the existence of epigenetic memory of transcriptional activation for genes that can be silenced by the Polycomb group. This property emerges during cell differentiation and allows genes to be stably switched after a transient transcriptional stimulus. This transcriptional memory state at Polycomb targets operates in cis; however, rather than relying solely on read-and-write propagation of histone modifications, the memory is also linked to the strength of activating inputs opposing Polycomb proteins, and therefore varies with the cellular context. Our data and computational simulations suggest a model whereby transcriptional memory arises from double-negative feedback between Polycomb-mediated silencing and active transcription. Transcriptional memory at Polycomb targets thus depends not only on histone modifications but also on the gene-regulatory network and underlying identity of a cell.

基因表达状态的表观遗传使单个基因组能够保持不同的细胞特性。组蛋白修饰如何促成这一过程仍不清楚。使用全局染色质扰动和局部、时间控制的转录调制，我们确定了可被 Polycomb 组沉默的基因转录激活的表观遗传记忆的存在。这种特性在细胞分化过程中出现，并允许基因在瞬时转录刺激后稳定切换。Polycomb 目标处的这种转录记忆状态以顺式方式运行; 然而，记忆不仅仅依赖于组蛋白修饰的读写传播，还与激活输入反对 Polycomb 蛋白的强度有关，因此随细胞环境而变化。我们的数据和计算模拟提出了一个模型，其中转录记忆产生于 Polycomb 介导的沉默和活跃转录之间的双负反馈。因此，Polycomb 靶点的转录记忆不仅取决于组蛋白修饰，还取决于基因调控网络和细胞的潜在身份。