AsianScientist (Feb. 23, 2016) – Researchers have developed a mathematical model that can be used to predictably ‘tune’ gene expression like a volume control knob. This work, published in Nature Genetics, has important implications in cellular and developmental biology, with potential applications in stem cell reprogramming and regenerative medicine.
Transcription factors are proteins that bind to special regions of DNA called enhancers so as to regulate gene expression. Some transcription factors activate gene expression, while others repress it. Gene expression level can be thought of like the volume of a radio: some transcription factors turn the volume up, while others turn it down.
Similar to how turning the volume knob of a radio allows us to regulate how loud or soft the music will be, each transcription factor has its own ‘volume knob,’ except that multiple transcription factors control each gene. The challenge is to understand how they all work together to produce the right volume.
The mathematical model developed by Dr. Garth Ilsley at the Okinawa Institute of Science and Technology Graduate University does not require information about the number and position of transcription factors binding to the enhancer to predict the level of gene expression.
Instead, the model correctly predicts the final volume only by knowing how the volume knobs are turned. These predictions were tested experimentally using artificial transcription factors that activate and repress gene expression with different strengths.
Working with fruit fly (Drosophila melanogaster) early stage embryos, the mathematical model showed that expression of genes that determine segmentation of the fruit fly body from head to tail is tunable.
Experimental results also matched the model’s prediction, showing that artificial activators and repressors can increase and decrease gene expression gradually in a way that is controllable and reproducible. This is akin to attaching yet another volume knob to the radio and finding that it works in concert with the existing knobs.
Beyond gene expression level, the model was also able to predict which location in the embryo—for example, ventral or dorsal—the gene would be expressed.
“It was our dream to bring model and experiment together,” enthused Ilsley.
“We are moving away from having to use an on/off model of gene expression to understand how cell types are specified. Advances in quantitative biology at the single-cell level, like quantitative imaging and RNA sequencing, together with mathematical models, now give biologists the tools they need to delve into the intricacies of gene expression tuning and to predictably manipulate the cell.”
The article can be found at: Crocker et al. (2016) Quantitatively Predictable Control of Drosophila Transcriptional Enhancers In Vivo with Engineered Transcription Factors.
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Source: Okinawa Institute of Science and Technology Graduate University.
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