Transient histone deacetylase inhibition induces cellular memory of gene expression and three-dimensional genome folding

Epigenetic memory enables the stable propagation of gene expression patterns in response to transient developmental and environmental stimuli. Although three-dimensional (3D) organisation is emerging as a key regulator of genome function, 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 histone acetylation and methylation, as well as global and local genome folding. While most epigenomic and transcriptional changes are readily reversible once the perturbation is removed, genome architecture partially maintains its perturbed conformation. This is significant, as a second transient pulse of hyperacetylation induces continued gene expression deregulation at hundreds of loci. Using ultra-deep Micro-C, we associate memory of gene expression with enhancer-promoter contacts and repressive chromatin topology mediated by Polycomb. These results demonstrate how cells are able to record a transient stress in their 3D genome architecture, enabling them to respond more robustly in a second bout of the same perturbation.