Modeling epigenome folding: formation and dynamics of topologically associated chromatin domains

Genomes of eukaryotes are partitioned into domains of functionally distinct chromatin states. These do-mains are stably inherited across many cell gener-ations and can be remodeled in response to devel-opmental and external cues, hence contributing to the robustness and plasticity of expression patterns and cell phenotypes. Remarkably, recent studies in-dicate that these 1D epigenomic domains tend to fold into 3D topologically associated domains forming specialized nuclear chromatin compartments. How-ever, the general mechanisms behind such compart-mentalization including the contribution of epige-netic regulation remain unclear. Here, we address the question of the coupling between chromatin fold-ing and epigenome. Using polymer physics, we ana-lyze the properties of a block copolymer model that accounts for local epigenomic information. Consid-ering copolymers build from the epigenomic land-scape of Drosophila, we observe a very good agree-ment with the folding patterns observed in chro-mosome conformation capture experiments. More-over, this model provides a physical basis for the existence of multistability in epigenome folding at sub-chromosomal scale. We show how experiments are fully consistent with multistable conformations where topologically associated domains of the same epigenomic state interact dynamically with each other. Our approach provides a general framework to improve our understanding of chromatin folding during cell cycle and differentiation and its relation to epigenetics