Abstract
Cell fate transitions are fundamental processes in the ontogeny of multicellular organisms1 and aberrations can generate pathologies2. Cell fate acquisition is a highly complex phenomenon which involves a plethora of intrinsic and extrinsic instructivesignals that direct the lineage progression of pluripotent cells. Previously, we defined thedynamic gene regulatory networks underlying neuronal differentiation induced by themorphogen all-trans retinoic acid (RA)3. Here we reveal the signal-propagating role ofthe chromatin interactome in the commitment and propagation of the initiating signal inearly neurogenesis by reconstructing dynamic loop-enhanced Gene Regulatory Networks(eGRNs) that integrate transcriptome, chromatin accessibility and long-range chromatininteractions in a temporal dimension. We observe a highly dynamic re-wiring ofchromatin interactions already at very early stages of neuronal differentiation. Long-range chromatin interactions are massively reorganized; only 30% of the initial interactome is conserved through cell differentiation, while new interactions are established already 6 hours after induction of neurogenesis. By integration of chromatin interactions together with temporal epigenome and transcriptome data, we identify a group of key regulatory elements that respond to and propagate the initial signal. Our data reveal an enormous capacity of the morphogen to reorganize long-range chromatin interactions by “reading” distant epigenetic signals and chromatin accessibility to drive cell fate acquisition. These results suggest that the differential establishment of chromatin contacts directs the acquisition of cell fate.