63 / 2026-04-03 15:29:31

Pioneer transcription factors direct cohesin chromatin entry and 3D genome organization

Loop extrusion, Cohesin, NIPBL, Pioneer factors, FOXA1

Cohesin complex organizes three-dimensional (3D) genome architecture by extruding DNA loops, but the mechanisms specifying its chromatin entry sites remain unclear. Motif and ChIP-seq analyses identify pioneer transcription factors (TFs), particularly FOXA1, as key mediators of the tissue-specific NIPBL recruitment to chromatin. FOXA1 directs NIPBL to intra-topologically associating domain (TAD) regions, enabling symmetric loop extrusion, while factors like ETS1 guide NIPBL to TAD boundaries, supporting asymmetric extrusion. Rapid depletion of FOXA1 disrupts NIPBL binding and selectively impairs intra-TAD loops, while loss of NIPBL reduces both intra-TAD and boundary-to-boundary interactions, highlighting their hierarchical roles in 3D genome folding. A recurrent FOXA1 mutation (R219S) in prostate cancer redirects FOXA1-NIPBL to TAD boundaries by recognizing a non-canonical motif, fostering a more insulated and tumor-aggressive genome. Evolutionary analysis points to a potential conserved role for TF-NIPBL cooperation in cohesin chromatin entry across species with tissue-specific adaptations. These findings reveal that pioneer factors orchestrate cohesin loading to shape tissue-specific 3D genome dynamics, a mechanism co-opted in cancer to rewire gene expression.