Forgetting isn’t all about loss. Sometimes, it’s about gain. For example, letting go of possibilities, really letting go, can solidify commitment. That’s how it is for cells when they progress from stage to stage during their development. Before committing to a new stage, a cell faces a decision—and it isn’t a snap decision, either, not for embryonic stem cells. It is reversible, for a time, owing to a peculiar give and take that occurs between an extracellular signaling pathway and the cell’s transcriptional machinery.

According to researchers from the Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) at the University of Copenhagen, embryonic stem cells can lose the potential to develop into any kind of cell if they “forget their past.” And this act of forgetting depends on a newfound capability displayed by transcription factors.

For 30 years, the dogma has been that transcription factors are the engines of gene expression, triggering developmental changes by switching genes on and off. However, new research results that appeared November 6 in a Nature article (“Dynamic lineage priming is driven via direct enhancer regulation by ERK”) reveal something quite different.

The question of how a cell slowly develops from one state to another is key to understanding cell behavior in multicellular organisms. Stem cell researchers consider this vital, which is why they are constantly trying to refine techniques to develop the human body’s most basic cells into various specific types of cells that can be used, for example, to regenerate damaged tissue. So far, however, investigating the signals required to make cells switch identity has been extremely difficult, since making all the cells in a dish do the same thing at the same time is very difficult.

The findings detailed in the new article could help researchers answer fundamental questions about cells’ developmental fates—how they are determined when nature runs its course, and how they may be deliberately altered.

“In this project, we focused on the fibroblast growth factor (FGF)-extracellular signal-regulated kinase (ERK) signaling pathway, which is a signaling pathway from a receptor on the surface of a cell to DNA inside the cell nucleus,” noted Joshua M. Brickman, PhD, professor and group leader, DanStem, and senior author of the Nature article. “This pathway is dysregulated in many types of cancer, and we, therefore, hope that many of the data in this study will help to inform aspects of cancer biology by indicating new ways to specifically target this signaling pathway in cancer cells.”

The researchers developed a stem cell model to mimic a cell’s response to signaling and used it to, for the first time, precisely determine the sequence of the events involved in a gene being turned on and off in response to a signal in stem cells. The researchers were able to describe how genes are turned on and off and under what circumstances a cell can develop in a certain direction but then elect to return to the starting point.

Part of this work involved measuring how proteins in a cell are modified by phosphorylation using advanced mass spectrometry available through a collaboration with Jesper Olsen’s group at the Novo Nordisk Foundation Center for Protein Research.

“Here we find that ERK reversibly regulates transcription in embryonic stem cells by directly affecting enhancer activity without requiring a change in transcription factor binding,” wrote the article’s authors. “ERK triggers the reversible association and disassociation of RNA polymerase II and associated co-factors from genes and enhancers. Though the binding of mediator components responds directly to signaling, the persistent binding of pluripotency factors to both induced and repressed genes marks them for activation and/or reactivation in response to fluctuations in ERK activity.”

These results are surprising. Although the sequence of cell transcription processes could not previously be measured as accurately as in this study, the dogma was that transcription factors comprise the on-off switch that is essential to initiate transcription of the individual gene. This is not so for embryonic stem cells and potentially for other cell types.

“Transcription factors are still a key signal, but they do not drive the process, as previously thought,” explained the paper’s first author, William Hamilton, assistant professor at DanStem. “Once they are there, the gene can be read, and they remain in place for a while after the gene is read. And when they are gone, the window in which the gene can be read can be closed again.

“You can compare it with the vapor trails you see in the sky when an airplane has passed. They linger for a while but slowly dissipate again.” The cellular analog to this dissipation? The reduction of pluripotency transcription factors by protein turnover.

“We previously thought that transcription factors drive the process that determines whether a gene is expressed and subsequently translated into the corresponding protein,” added Brickman. “Our new results show that transcription factors may be more analogous to being the memory of the cell. As long as the transcription factors are connected to a gene, the gene can be read (turned on), but the external signals received by the cells seem to determine whether the gene is turned on or off. As soon as the transcription factors are gone, the cells can no longer return to their point of origin.”

The new findings, which challenge fundamental assumptions in molecular biology, are especially important for researchers working on stem cells and cancer biology. They provide new insight into how cells develop, how pathways involved in development determine when cells change, and when the point of no return is reached. These pathways are also found frequently mutated in cancer; consequently, the new findings will be valuable to the study of malignant development.

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