Cells are more resilient to environmental changes than previously thought

Cells are more resilient to environmental perturbations than previously thought. Observations of the effects of drugs or mutations on cells grown in a lab setting indicate that they overcome external influences and provide a solid basis for developing new diagnostics and treatments.

A group of researchers, including ICREA researcher Dr. Patrick Aloy, head of the Structural Bioinformatics and Network Biology lab at IRB Barcelona, and Dr. Carles Pons, Ramón y Cajal research associate in the same lab, have published a study in the journal Science showing that Baker’s yeast cells use the same gene interaction network to coordinate growth in response to a wide range of environments.

“We wanted to test in an unbiased way how the reference genetic network of a model cell changes in different environments,” says Dr. Brenda Andrews, former director of the Donnelly Centre who co-led the research. “And we found that the network is highly resilient and remains broadly the same, which means that a single reference condition provides us with a nearly complete view of the molecular wiring of a cell.” Dr. Charles Boone, a Professor of Molecular Genetics and interim Director of the centre, and Dr. Chad Myers, a professor of computer science at the University of Minnesota-Twin Cities, were also senior authors of the paper.

“We have contributed to this work by characterizing the responsive genes to environmental changes and by analysing the functional coherence of the discovered genetic interactions in the different tested conditions” says Dr. Aloy.

The work builds on previous research that established how yeast’s ~6000 genes form a network of ~900,000 interactions. Yeast cells are similar to human ones but they are easier to study because they have smaller genomes and there are well-established techniques for their genetic manipulation. This explains why scientists have been using these cells as a research model to study the molecular foundations of life.

“As the only genome-wide map of genetic interactions for any cell, the global yeast genetic network is a unique reference resource. The interactions between genes provide clues about their function, and they can also reveal how mutations combine to cause the cellular defects underlying diseases,” says Dr. Pons. “A robust reference map is also key for identifying the best genes to target therapeutically,” he adds.

There was concern, however, that genes might change their interacting partners depending on the cellular environment, which would complicate things because it would mean that the molecular wiring is dynamic, like a moving target. The reference map was constructed from data collected under standard laboratory conditions, but alteration of the conditions may affect the network.

Others have reported that the environment can rewire the interactions within a select group of genes involved in a specific cellular process, such as DNA repair, but its impact across the genome had not been assessed systematically.

A representative set of genes and environments

Two genes are said to interact when cells lacking both genes grow better or worse than when only one is absent. The testing of all possible pairwise interactions that led to the creation of the reference map took over 15 years and cost tens of millions of dollars in research funding. Since it would have been impossible to replicate this tour de force under multiple conditions, the researchers selected a representative set of genes that span all major biological processes. In total, 30,000 genome-wide interactions were tested under 14 diverse environments, including an alternate food source, osmotic pressure, as well as exposure to various drugs.

The vast majority—more than 90%—of the interactions first identified in the reference map persisted across all the conditions. Only 7% of the interactions were novel, meaning they were detected for the first time and only in some environments. These novel interactions typically occurred between genes involved in several cellular processes, thereby revealing that external stimuli have the power to forge more distant genetic interactions.

The team is now working to create the first human reference map—a huge task given the larger number of genes involved (~20,000) and the 200 million possible interactions between them. But the researchers say that, based on their yeast work, they are confident that the human map will equally capture the fundamental biology regardless of variables such as cell type or growth conditions.

Reference article:
Environmental robustness of the global yeast genetic interaction network
Michael Costanzo, Jing Hou, Vincent Messier, Justin Nelson, Mahfuzur Rahman, Benjamin VanderSluis, Wen Wang, Carles Pons, Catherine Ross, Matej Ušaj, Bryan-Joseph San Luis, Emira Shuteriqi, Elizabeth N. Koch, Patrick Aloy, Chad L. Myers, Charles Boone & Brenda Andrews
Science (2021) DOI: 10.1126/science.abf8424

Source: Jovana Drinjakovic (Donnelly Centre for Cellular and Biomolecular Research)