The epigenome and three-dimensional (3D) genomic architecture are emerging as key factors in the dynamic regulation of different transcriptional programs required for neuronal functions. In this study, we used an activity-dependent tagging system in mice to determine the epigenetic state, 3D genome architecture and transcriptional landscape of engram cells over the lifespan of memory formation and recall. Our findings reveal that memory encoding leads to an epigenetic priming event, marked by increased accessibility of enhancers without the corresponding transcriptional changes. Memory consolidation subsequently results in spatial reorganization of large chromatin segments and promoter–enhancer interactions. Finally, with reactivation, engram neurons use a subset of de novo long-range interactions, where primed enhancers are brought in contact with their respective promoters to upregulate genes involved in local protein translation in synaptic compartments. Collectively, our work elucidates the comprehensive transcriptional and epigenomic landscape across the lifespan of memory formation and recall in the hippocampal engram ensemble.

表观基因组和三维（3D）基因组结构正在成为神经元功能所需的不同转录程序动态调节的关键因素。在这项研究中，我们在小鼠中使用了活动依赖性标记系统来确定记忆形成和回忆整个生命周期中印迹细胞的表观遗传状态、3D 基因组结构和转录景观。我们的研究结果表明，记忆编码会导致表观遗传启动事件，其特点是增强子的可及性增加，而没有相应的转录变化。记忆巩固随后导致大染色质片段的空间重组和启动子-增强子相互作用。最后，通过重新激活，印迹神经元使用从头长程相互作用的子集，其中引发的增强子与其各自的启动子接触，以上调参与突触区室中局部蛋白质翻译的基因。总的来说，我们的工作阐明了海马印迹群中记忆形成和回忆整个生命周期的全面转录和表观基因组景观。