Split-Broccoli is modular and can be used to monitor RNA–RNA
hybridization events in vivo. (a) A Split-Broccoli
Toehold Switch plasmid was constructed to include two constitutively
expressed transcription units. The first transcription unit encodes Top (yellow) and Toehold (gray) sequences
within the 5′ UTR of the mCherry mRNA (red).
Translation of the Top-Toehold-mCherry mRNA is suppressed
due to sequestration of the ribosome binding site (orange) and start
codon within the toehold structure (boxed). The second transcription
unit encodes Trigger (gray) and Bottom (blue) sequences, which can base pair with Top-Toehold-mCherry. (b) Hybridization of Top-Toehold-mCherry with Trigger-Bottom allows fluorescence activation of the Split-Broccoli
system and translation of mCherry. (c) Green fluorescence
(left columns) and red fluorescence (right columns) from flow cytometric
analysis of populations show background levels of fluorescence for
plasmids encoding a single transcription unit only (Top-Toehold-mCherry or Trigger-Bottom). Top + Bottom, which transcribes the Split-Broccoli system, exhibits only green
fluorescence, while the Split-Broccoli Toehold Switch plasmid (Top-Toehold-mCherry + Trigger-Bottom) exhibits
both red and green fluorescence, indicating both hybridization of
Split-Broccoli and translation of mCherry. Grand
mean fluorescence intensity (n = 4) is shown with
error bars to indicate standard deviations. (d) Fluorescence microscopy
imaging of E. coli harboring the Split-Broccoli
Toehold Switch plasmid confirms hybridization of the Top and Bottom
components of Split-Broccoli (green fluorescence)
and activation of mCherry translation (red fluorescence).
(e) An E. coli cell-free system (TX-TL) was
used to monitor transcription and translation of the Split-Broccoli
Toehold Switch plasmid and demonstrates the increased temporal sensitivity
of Split-Broccoli (green fluorescence, left axis)
over mCherry (red fluorescence, right axis). Mean
values (n = 3) are shown with error bars to indicate
standard deviations.