Dynamic alterations in genome conformation establish blueprints of developmental gene expression. These changes reflect a 4-dimensional (4D) orchestration of temporal gene regulation in the nucleus space. We report large-scale 4D changes in genome conformation occurring during commitment of human mesenchymal stem cells into adipogenic and neuronal lineages. We combine maps of topologically-associated domains (TADs) and lamin-associated domains (LADs), together with a 3D genome modeling tool (Chrom3D) [1], to infer TAD position in space during bi-lineage differentiation. Whereas TAD boundaries are stable along the linear genome, TADs show temporal dynamics in space. We unveil the formation of multiple TAD-TAD associations into multi-megabase repressive hubs, or TAD cliques. Most TAD cliques are constitutive; however others assemble or break apart in a lineage-specific manner. We highlight adipogenic- and neurogenic-specific transient TAD cliques engulfing or releasing cell cycle, adipogenic or neurogenic loci. Through associations with the nuclear lamina, TAD clique assembly or growth draws genic regions into a repressive environment at the nuclear periphery. LADs appear as facilitators of long-range TAD repositioning in the nucleus space that establish new TAD clique patterns. Lineage-specific dynamic TAD cliques highlight a new level of developmental genome organization. Our findings provide an overview of large-scale changes in the 4D nucleome during lineage-specific differentiation. Lastly, we are developing virtual reality (VR) genomics, enabling interactive spatial exploration of the genome. VR genomics shows potential for analysis and educational purposes.
[1] Paulsen et al. 2017. Genome Biol 18, 21.