A recently developed computer program, unveiled by the Gargiulo lab at the Max Delbrück Center and reported in Nature Communications, allows scientists to design synthetic DNA segments indicating the real-time state of cells. Dubbed "Logical Design of Synthetic cis-regulatory DNA" (LSD), the algorithm generates tools called "synthetic locus control regions" (sLCRs), aiding in understanding cellular behavior and disease processes.
“This algorithm enables us to create precise DNA tools for marking and studying cells, offering new insights into cellular behaviors,” says Gargiulo, senior author of the study. “We hope this research opens doors to a more straightforward and scalable way of understanding and manipulating cells.”
Researchers input the known genes and transcription factors associated with the specific cell states they want to study, and the program uses this to identify DNA segments (promoters and enhancers) controlling the activity in the cell of interest. This information is sufficient to discover functional sequences, and scientists do not have to know the precise genetic or molecular reason behind a cell’s behavior; they just have to construct the sLCR.
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The resulting sLCRs, integrated with fluorescent proteins, act as "automated lamps" inside cells, indicating specific states under study. The color of the “lamp” can be varied to match different states of interest, so that scientists can look under a fluorescence microscope and immediately know the state of each cell from its color.
The team has validated the utility of the computer program by using it to screen for drugs in SARS-CoV-2 infected cells. They also used it to find mechanisms implicated in glioblastomas, where no single treatment works. “In order to find treatment combinations that work for specific cell states in glioblastomas, you not only need to understand what defines these cell states, but you also need to see them as they arise,” says Dr Matthias Jürgen Schmitt, co-first author of the study.