Adaptation by stochastic tuning of gene expression in mammalian cells

Cells often face environmental challenges for which they lack pre-programmed regulatory responses. We have previously shown that yeast cells can, nevertheless, adapt to such unfamiliar conditions by a phenomenon we have termed stochastic tuning. In this process, cells use gene expression noise to randomly change the expression of individual genes and actively reinforce those changes that improve the overall health of the cell. Here, we provide experimental evidence for stochastic tuning in human cells adapting to the lethal chemotherapeutic agent methotrexate. As in yeast, the tuning process is not driven by mutations and is reversible upon removal of methotrexate challenge. We show that stochastic tuning is a conserved eukaryotic mechanism of cellular adaptation, and potentially a key factor in the phenomenon of cancer cell plasticity underlying chemotherapy resistance.