Multi-scale 3D genome rewiring during mouse neural development

Chromosome conformation capture technologies have revealed important insights into genome folding. Yet, how spatial genome architecture is related to gene expression and cell fate remains unclear. We mapped comprehensively 3D chromatin organization during mouse neural differentiation in vitro and in vivo, generating the highest resolution Hi-C maps available to date. We found that transcription is correlated with chromatin insulation and long-range interactions, but dCas9-mediated activation is insufficient for creating topological domain (TAD) boundaries de novo. Additionally, we discovered long-range contacts between gene bodies of exon-rich, active genes in all cell types. During neural differentiation, contacts between active TADs become less pronounced while inactive TADs interact stronger. An extensive Polycomb network in stem cells is disrupted, while dynamic interactions between proneural transcription factors appear in vivo. Finally, cell-type specific enhancer-promoter contacts are established concomitant to gene expression. This work shows that multiple factors influence the dynamics of chromatin interactions in development.