High-throughput screening plates. Image credit: Heigwer et al. (CC BY 4.0)
Within a cell, communication routes that involve many different genes work to control how the cell responds to the environment. Although different communication routes – so called signaling pathways – control different cell activities, they do not work in isolation. Instead, they form part of larger regulatory networks that maintain the cell in an appropriate state. As such, changing the activity of one pathway may in turn affect another seemingly unrelated pathway.
The Ras signaling pathway helps to control when cells divide. When this signaling is not regulated correctly, cells can start to divide uncontrollably, leading to cancer. Drugs that suppress the activity of overactive Ras pathways could help to treat cancer. But how do the wider regulatory networks in the cell rewire themselves over time in response to this treatment?
To investigate this question, Heigwer et al. used a method called RNA interference to alter the activity of different pairs of 168 genes in fruit fly cells that had been grown in the laboratory. This meant 12,768 gene interactions were examined in total. Some of the cells had been treated with a drug that suppresses Ras signaling. By developing a new cell imaging and analysis system, Heigwer et al. could examine how the cell’s regulatory networks were affected by the drug at three different time points after treatment. The results show that housekeeping genes, which handle basic cell duties, take more time to rewire their interactions than signaling pathways.
Heigwer et al. also developed a computational method – called MODIFI – to analyze how environment and time affect how genes interact. This highlighted a number of signaling pathways that are strongly affected by the suppression of Ras signaling, including an unexpected immune signaling pathway.
In the future, more research will be needed to study the context-dependency of interactions between genetic networks in different cell types and in living organisms. A better understanding of this context-dependency will be important to understand how cancerous cells develop drug resistance. The data collected by Heigwer et al. could also be used by other researchers to explain any unexpected gene interactions that affect the signaling pathways they are studying.
