Function of Steroid Receptors in Subcellular Compartments

Division Of Basic Sciences - Nci

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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 discovered 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 demonstrated that the glucocorticoid receptor interacts with NIPBL and the cohesin complex at the chromatin level, promoting loop extrusion and long-range gene regulation. Real time single molecule experiments showed that cohesin-mediated loops entrap TFs molecules at specific nuclear confinement sites, increasing TF local concentration and promoting gene regulation. Finally, patient-derived acute myeloid leukemia cells harboring cohesin mutations exhibit a reduced response to glucocorticoids (GCs), suggesting that the GR-NIPBL-cohesin interaction is defective in these patients, resulting in poor response to GC treatment.