A histone hyperacetylation pulse induces cellular memory of gene expression and 3-dimensional genome folding [microC_1]

Epigenetic memory enables the stable propagation of gene expression patterns in response to transient developmental and environmental stimuli. Although 3-dimensional (3D) organisation is emerging as a key regulator of genome function due its role in gene expression control, it is unknown whether it contributes to cellular memory. Here, we establish that acute perturbation of the epigenome can induce cellular memory of gene expression in mouse embryonic stem cells (mESCs). Specifically, we uncover how a pulse of histone deacetylase inhibition translates to changes in the histone acetylation and methylation landscape, as well as global and local genome folding. While most epigenomic and transcriptional changes are readily reversible once the perturbation is removed, architectural features are not fully reestablished. Upon a second transient pulse of hyperacetylation, hundreds of genes maintain their dysregulated state. Using ultra-deep Micro-C, we associate memory of gene expression with enhancer-promoter contacts and repressive chromatin topology mediated by Polycomb. These results uncover the complex interplay between different epigenetic regulatory layers and establish a novel link between genome folding and cellular memory. Micro-C experiments in mouse ESCs in control (DMSO), TSA-treated or 24-hour recovery (REC) conditions.

表观遗传记忆（Epigenetic memory）可使基因表达模式在应对瞬时发育与环境刺激时实现稳定传递。尽管三维基因组组织（3-dimensional organisation）因参与基因表达调控而逐渐成为基因组功能的关键调控因子，但目前尚不明确其是否对细胞记忆具有贡献。本研究证实，表观基因组的急性扰动可在小鼠胚胎干细胞（mouse embryonic stem cells, mESCs）中诱导基因表达相关的细胞记忆。具体而言，本研究揭示了组蛋白去乙酰化酶抑制剂的短时脉冲处理如何引发组蛋白乙酰化与甲基化谱的改变，以及全局与局部基因组折叠的变化。尽管在扰动移除后，大多数表观基因组与转录组变化可快速恢复，但基因组结构特征却无法完全重建。当再次施加瞬时的高乙酰化刺激时，数百个基因仍维持其失调状态。本研究利用超深度Micro-C技术，将基因表达记忆与增强子-启动子相互作用以及由多梳蛋白（Polycomb）介导的抑制性染色质拓扑结构关联起来。上述研究结果揭示了不同表观遗传调控层级间的复杂相互作用，并建立了基因组折叠与细胞记忆之间的全新关联。本研究的Micro-C实验以小鼠胚胎干细胞为对象，涵盖对照组（二甲基亚砜，DMSO）、曲古抑菌素A（TSA）处理组以及24小时恢复（REC）组三种实验条件。