Fig. 4

Crosstalk modes at the DNA level. At the DNA level, nuclear receptors engage in crosstalk by indirectly or directly interacting with DNA. Part a outlines indirect regulation modes, where no physical interaction occurs, whereas Part b describes regulatory mechanisms involving direct physical interactions among nuclear receptors (NRs). Indirect regulation modes include: NR signaling pathways may compete for overlapping DNA-binding sites; NR heterodimer partners may cause redistribution or squelching; Components of the transcriptional machinery, such as RNA polymerase II (Pol II) and transcriptional coregulators, may cause redistribution or squelching; The alteration of shared coregulators can influence the activity of other NRs. One NR family member can act as a pioneering factor to facilitate chromatin loosening and enable the subsequent binding of other NRs. Direct physical interactions includes: Paired receptors may cooperate for direct DNA binding or through DNA looping; Direct crosstalk can occur with just one partner contacting the DNA; Two nuclear receptors engage in crosstalk through protein-protein interactions with other transcription factors (TFs); The sequestration of one or both NRs (originating from other modes, (f–i) away from the DNA due to heterodimer interactions