Integrated analyses of 3D genome dynamics during neurodifferentiation reveal multiple reorganization routes. Integrated analyses of 3D genome dynamics during neurodifferentiation reveal multiple reorganization routes

The three-dimensional (3D) spatial organization of the genome is a key epigenetic property intimately linked with transcription and genome stability. How the 3D genome is reorganized during cell differentiation processes remains relatively poorly understood. Here, we describe a multi-omic approach to map the local and global 3D genome dynamics across three timepoints during the differentiation of human neuroepithelial stem (NES) and progenitor cells (NPC) to neurons (NEU) in vitro. We found that chromosome contact frequency changes measured by Hi-C occurred predominantly during the transition from NES to NPC, whereas radial changes probed by GPSeq prevail in the NPC to NES transition. Genes whose expression changed during the differentiation process appeared to be regulated either by changes in their interactome or by radial repositioning. Notably, genomic regions undergoing dynamic changes during differentiation from NES to NEU were significantly enriched in genes implicated in neurodevelopmental disorders. Our analyses reveal that, during neurodifferentiation, the 3D genome undergoes different routes of local and global reorganization concurrently with dynamic changes in transcriptional and genome fragility landscapes.