Extensive long-range polycomb interactions and weak compartmentalization are hallmarks of human neuronal 3D genome

Summary Chromatin architecture regulates gene expression and shapes cellular identity, particularly in neurons. Here, we map the 3D genome architecture of neuronal and non-neuronal cells isolated from the human Wernicke’s area. Neurons display greatly reduced genome segregation into active and inactive compartments compared to other brain cells. Neuronal Hi-C maps reveal strong long-range interactions mediated by polycomb group (PcG) proteins, forming a unique network of contacts in neurons that is nearly absent in other brain cells. These interactions involve loci harboring developmental transcription factors repressed in neurons and other mature brain cells. Intriguingly, these loci exclusively in neurons contain bivalent promoters occupied by both H3K4me3 and H3K27me3 histone modifications, suggesting the functional role of PcG contacts in neurons. Furthermore, neurons exhibit distinctive organization at other layers of chromatin architecture, potentially attributed to elevated neuronal loop extrusion activity, which aligns with increased cohesin levels.