The glucocorticoid receptor associates with the cohesin loader NIPBL to promote long-range gene regulation
Lorenzo Rinaldi, Grégory Fettweis, Sohyoung Kim, David A. Garcia, Saori Fujiwara, Thomas A. Johnson, Theophilus T. Tettey, Laurent Ozbun, Gianluca Pegoraro, Michele Puglia, Blagoy Blagoev, Arpita Upadhyaya, Diana A. Stavreva, Gordon L. Hager
Abstract
The cohesin complex is central to chromatin looping, but mechanisms by which these long-range chromatin interactions are formed and persist remain unclear. We demonstrate that interactions between a transcription factor (TF) and the cohesin loader NIPBL regulate enhancer-dependent gene activity. Using mass spectrometry, genome mapping, and single-molecule tracking methods, we demonstrate that the glucocorticoid (GC) receptor (GR) interacts with NIPBL and the cohesin complex at the chromatin level, promoting loop extrusion and long-range gene regulation. Real-time single-molecule experiments show that loss of cohesin markedly diminishes the concentration of TF molecules at specific nuclear confinement sites, increasing TF local concentration and promoting gene regulation. Last, patient-derived acute myeloid leukemia cells harboring cohesin mutations exhibit a reduced response to GCs, suggesting that the GR-NIPBL-cohesin interaction is defective in these patients, resulting in poor response to GC treatment.