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Light-activated transcription and repression by using photocaged SERMs
1Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA.
Chembiochem : a European Journal of Chemical Biology
|June 3, 2004
Summary
Researchers developed photocaged selective estrogen receptor modulators (SERMs) for light-controlled gene expression. These compounds offer precise temporal and spatial control over gene activity, advancing research into gene function.
Area of Science:
- Molecular Biology
- Genetics
- Pharmacology
Background:
- Gene spatiotemporal patterning is crucial for biological functions.
- Photocaged ligands offer light-directed control over gene expression.
- Nuclear receptors play key roles in gene regulation.
Purpose of the Study:
- To evaluate photocaged analogues of selective estrogen receptor modulators (SERMs) for controlling gene expression patterning.
- To investigate the light-directed actions of photocaged SERMs on estrogen receptor (ER) activity.
- To explore the simultaneous control of transcription activation and repression using photocaged SERMs.
Main Methods:
- Synthesis of photocaged hydroxytamoxifen (NB-Htam) and guanidine tamoxifen (NB-Gtam).
- Evaluation of NB-Htam and NB-Gtam for antagonizing ER alpha- and ER beta-mediated transcription at estrogen response elements (EREs).
- Assessment of transcription recovery rates upon SERM diffusion from cells.
- Investigation of ER beta-mediated transcription activation at AP1 sites.
Main Results:
- NB-Htam and NB-Gtam selectively antagonize ER alpha and ER beta transcription in response to light.
- Intracellular Htam and Gtam induce transient transcriptional repression.
- Transcription recovery rates for Htam and Gtam are faster than for tamoxifen aziridine (Taz), suggesting ligand off-rates/diffusion control duration.
- Gtam activates ER beta-mediated transcription at AP1 sites.
- Photocaged SERMs enable light-activated transcription and repression simultaneously.
Conclusions:
- Photocaged SERMs provide precise light-directed control over gene expression.
- Ligand off-rates and diffusion, rather than receptor turnover, dictate the duration of SERM action.
- These tools allow for simultaneous light-activated transcription and repression, offering novel research capabilities.