Muscle cells and neurons are very different, both in form and function. And the critical genes that get switched on in order to shape each type of cell’s form and function are different too. Not surprisingly, the protein that orchestrates muscle-specific genes in muscle cells differs from a master regulator found in neurons. But this apparent complexity hides an unexpected simplicity, according to new research published today (March 19) in Cell Reports.
Scientists at Fred Hutchinson Cancer Research Center discovered that the power to turn precursor stem cells into muscle cells or neurons lies in one small section of the gene-orchestrating proteins. When they replaced this segment of the muscle-specific protein, called MyoD, with the corresponding segment from the neuronal protein, MyoD transformed into a protein that pushed cells down the path of neuronal development. The team’s findings could have wider implications for researchers looking to hobble the genetic programs cancer cells co-opt in order to grow unrestrainedly.
It’s a much less complicated system than Dr. Stephen Tapscott, who led the study, had anticipated. Faced with the incredible variety of structure and composition of proteins, he expected that other segments in MyoD would play a larger part in its role as a master of cell fate.
“It turns out it’s simpler than I thought,” said Tapscott, who investigates how mutations in the key proteins that turn genes on can affect cancer and muscular dystrophy. MyoD is what’s known as a transcription factor, a type of protein that is required for a gene to be expressed. They’re so named because they control the first step in the process of extracting genetic information, or transcribing it, so it can then be turned into proteins. Discovered almost 30 years ago at Fred Hutch by the late Dr. Harold "Hal" Weintraub, MyoD is what’s known as a “master regulator” because it controls the expression of all the essential genes that give muscle cells their distinctive qualities.
The critical section of MyoD, the part that is central to its identity as a muscle cell maestro, is its DNA-binding region, which controls where on the chromosomes it can attach — and which genes it turns on.
“Even though there are many other components of a transcription factor besides the region that targets it to DNA, those components, at least in some contexts, are relatively generic, and where the factor binds is the greatest determinant of the [genetic] program that it activates,” Tapscott said.
First author Dr. Abraham Fong tested the consequences of replacing MyoD’s DNA-binding region with the DNA-binding region from neurons’ master regulator, NeuroD2. MyoD and NeuroD2, though largely dissimilar, come from a related family of transcription factors. In fact, there is a common set of genes to which they can both bind, but differences between their DNA-binding regions allow each of the two proteins to also turn on their own unique sets of genes, which is what enables one to make muscle cells while the other makes neurons.
When Fong engineered a version of MyoD so that it only bound NeuroD2’s unique genes and the shared genes, he found that this one change was all it took to direct his chimeric MyoD to NeuroD2’s neuron-specific genes and convert MyoD into a master regulator of neuronal development.
The findings could have implications for tissue engineering or even cancer treatment, said Tapscott. In order to become a distinct cell type like a muscle cell or a neuron, cells must go through a series of developmental steps, each closer to the final cell type. When cells reach the final step, they stop dividing and fully commit to their new fate as, say, a muscle cell. Cancer cells, in contrast, often find a way to halt this process a few steps away from the end so that they can continue dividing without restraint.
In theory, researchers could make cancer cells stop dividing by forcing them to walk the final few steps. Tapscott and Fong’s results open up the possibility that instead of engineering entirely new master regulator proteins for every cancer type, scientists could instead create a generic transcription factor and merely tailor its DNA-binding region by tumor variety, similar to the way a power drill can be adapted by switching bits.
Tapscott pointed to an example in nature that indicates that his relatively simple model “should be generalizable to a degree.” In some instances of rhabdomyosarcoma, a rare cancer arising from muscle cells stalled in their journey toward their final non-dividing state, mutations to MyoD’s DNA-binding region redirect the factor from muscle-specific genes to genes that instead promote unrestrained growth and cancer development.
The researchers’ discovery suggests that it’s theoretically possible to tackle these tumors by fixing MyoD’s mutation and forcing the cancer cells to differentiate. However, Tapscott noted, the gene therapy techniques that such a strategy would require are far from ready for clinical use.
Tapscott cautioned against generalizing the findings too far, noting that nuances remain to be elucidated.
“Even though the study we’re presenting suggests a simple model, there is complexity superimposed on it,” he said, pointing to the variety found just in the DNA-binding domains of transcription factors. It remains to be seen whether other transcription factor families could swap DNA-targeting domains as easily as MyoD and NeuroD2, or whether these domains could be swapped between families. “We do anticipate that not all transcription factors will be ‘swappable,’ and there will be specific rules for specific families … The next-tier rules need to be further clarified,” Tapscott said.
But for researchers who might hope to steer cancer cell differentiation, this simple model could hold promise, he said: “The utility is there.”
Sabrina Richards is a staff writer at Fred Hutchinson Cancer Research Center. She has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at firstname.lastname@example.org.