Current approaches for optogenetic control of transcription
do not mimic the activity of endogenous
transcription factors, which act at numerous sites in
the genome in a complex interplay with other factors.
Optogenetic control of dominant negative versions
of endogenous transcription factors provides a
mechanism for mimicking the natural regulation of
gene expression. Here we describe opto-DN-CREB,
a blue-light-controlled inhibitor of the transcription factor CREB created by fusing the dominant negative inhibitor A-CREB to photoactive yellow protein (PYP). A light-driven conformational change in PYP prevents coiled-coil formation between A-CREB and CREB, thereby activating CREB. Optogenetic control of CREB function was characterized in vitro, in HEK293T cells, and in neurons where blue light enabled control of expression of the CREB targets NR4A2 and c-Fos. Dominant negative inhibitors exist for numerous transcription factors; linking these to optogenetic domains offers a general approach for spatiotemporal control of native transcriptional events.