| Zdroj: |
Rinaldi, L, Fettweis, G, Kim, S, Garcia, D A, Fujiwara, S, Johnson, T A, Tettey, T T, Ozbun, L, Pegoraro, G, Puglia, M, Blagoev, B, Upadhyaya, A, Stavreva, D A & Hager, G L 2022, ' The glucocorticoid receptor associates with the cohesin loader NIPBL to promote long-range gene regulation ', Science Advances, vol. 8, no. 13, eabj8360 . https://doi.org/10.1126/sciadv.abj8360 |
| Popis: |
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. |
