The glucocorticoid receptor associates with the cohesin loader NIPBL to promote long-range gene regulation

• DOI: 10.1126/sciadv.abj8360
• Publication Date: 2022-03-30T17:57:25Z
• Authors: Lorenzo Rinaldi; Gregory 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
• Keywords: 0301 basic medicine; 03 medical and health sciences; Receptors, Glucocorticoid; Gene Expression Regulation; Chromosomal Proteins, Non-Histone; Humans; Cell Cycle Proteins; Biomedicine and Life Sciences; Cohesins

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.