The evolution of the nucleus is an evolutionary milestone. By enabling genome compartmentalization, it contributes to the fine-tuning of genome functions. The genome is partitioned into functional domains differing in spatial positioning and topological folding at different scales. The rise of '3D Genomics' embracing experimental, theoretical, and modeling approaches allowed the proposal of a multiscale model of the eukaryotic genome, capturing its organizing principles and functionalities. In these efforts, resolving causality remains an important objective. Are positioning and folding the cause or consequence of functional states? This minireview presents emerging answers to this question, borrowing examples from recent studies of the three-dimensional genome in both plants and animals.