Light‐Activated Transcription and Repression by Using Photocaged SERMs

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Abstract
Recently developed methods to regulate the spatial and temporal patterning of genes in a light‐directed manner hold promise as powerful tools for exploring the function of genes that act through their unique spatiotemporal patterning. To further explore the application of photocaged ligands of nuclear receptors to control gene expression patterning, the actions of photocaged analogues of selective estrogen‐receptor modulators (SERMs) have been evaluated. Photocaged derivatives of hydroxytamoxifen (NB‐Htam) and guanidine tamoxifen (NB‐Gtam) have been synthesized that selectively antagonize ERα‐ and ERβ‐mediated transcription at classic estrogen response elements (EREs) in response to light. When present only intracellularly, Htam and Gtam provide a similar transient repression response. When SERMs are allowed to diffuse out of the cell, transcription is recovered at a similar rate for Htam and Gtam (6.4 and 5.6 h−1), but is notably faster than is observed with the covalently binding SERM tamoxifen aziridine (Taz) (3.8 h−1). This suggests that the duration of agonist action is controlled by ligand off‐rates/diffusion and not by receptor turnover. Gtam activates ERβ‐mediated transcription at AP1 sites in a similar way to what has previously been reported for Htam. NB‐Gtam and NB‐Tam provide a light‐activated transcription response at AP1‐driven reporters, thus illustrating the unique ability of photocaged SERMs to simultaneously mediate light‐activated transcription and repression.