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Bioengineers at the University of California San Diego have developed a genome-scale reference map showing how individual genes control the functions and identities of human induced pluripotent stem cells. Published in Nature Biotechnology, the open-access resource is designed to support researchers building virtual cell models for complex diseases and designing patient-specific treatments.
Senior author Prashant Mali described the resource as a reference atlas. “"The result is a kind of reference atlas; it’s a way to look up what perturbing almost any gene does to a stem cell's behavior, measured here as the impact on its whole transcriptome,” Mali said.
The atlas represents the first genome-scale map of gene function in human induced pluripotent stem cells. Because so little is understood about what most human genes actually do inside these cells, the researchers set out to close that gap. Using CRISPR technology, the team systematically switched off 11,692 expressed genes one at a time and measured the resulting effects across more than 2.5 million single cells.
From this dataset, the researchers grouped related genes and cellular components according to shared molecular traits and functions, which allowed them to isolate previously hidden metabolic and self-renewal genes. The map also led to the discovery of previously unrecognized cell regulators, which the team confirmed experimentally. Among these findings, the gene DBR1 was identified as the main regulator of RNA editing, specifically the conversion of adenosine to inosine.
First author Yesh Doctor explained how the map could be applied. “The map we generated works as a hypothesis engine—it’s a starting point for what a given gene does and which genes might be worth pursuing as targets to drive differentiation into cell states of interest,” Doctor said. “Scientists can use it to look up the functions of genes and build hypotheses on them instead of having to run the experiments themselves.”
Senior author Prashant Mali described the resource as a reference atlas. “"The result is a kind of reference atlas; it’s a way to look up what perturbing almost any gene does to a stem cell's behavior, measured here as the impact on its whole transcriptome,” Mali said.
The atlas represents the first genome-scale map of gene function in human induced pluripotent stem cells. Because so little is understood about what most human genes actually do inside these cells, the researchers set out to close that gap. Using CRISPR technology, the team systematically switched off 11,692 expressed genes one at a time and measured the resulting effects across more than 2.5 million single cells.
From this dataset, the researchers grouped related genes and cellular components according to shared molecular traits and functions, which allowed them to isolate previously hidden metabolic and self-renewal genes. The map also led to the discovery of previously unrecognized cell regulators, which the team confirmed experimentally. Among these findings, the gene DBR1 was identified as the main regulator of RNA editing, specifically the conversion of adenosine to inosine.
First author Yesh Doctor explained how the map could be applied. “The map we generated works as a hypothesis engine—it’s a starting point for what a given gene does and which genes might be worth pursuing as targets to drive differentiation into cell states of interest,” Doctor said. “Scientists can use it to look up the functions of genes and build hypotheses on them instead of having to run the experiments themselves.”