In this chapter, the authors review their efforts to understand the functional coupling between the three-dimensional (3D) dynamical organization of chromatin and the 1D segmentation of genome into active and inactive domains using polymer and statistical physics modeling. They discuss how polymer modeling allows them to better understand the coupling between epigenome and 3D chromosome organization. The observed correlations between epigenome and contactome suggest the existence of epigenomic-specific mechanisms playing major roles in chromatin folding. The authors develop several methods to investigate the behavior of the block copolymer model of chromatin. In the context of epigenomics, the nano-reactor hypothesis naturally introduces a functional coupling between 3D organization and 1D epigenomic state. In order to progress toward a quantitative description of this 1D–3D coupling, a correct parameter inference would require experiments that can record the large-scale dynamics of both the 1D and 3D organization, during the establishment and the maintenance stages, in both wild-type and mutant backgrounds.