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

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 initially reversed 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.