Every cell in your body contains the same DNA, with genes coding for many thousands of proteins. Yet a muscle cell makes a very different set of proteins from say, a bone cell, enabling it to perform its muscle-specific job. Lorenzo Puri, M.D., Ph.D. and his lab members study what makes stem cells (precursor cells) choose to produce the proteins that turn them into muscle cells. In doing so, they hope their research will one day help improve strategies for muscle regeneration in patients with muscle wasting diseases, such as muscular dystrophy. While a cure for muscular dystrophy is not yet in sight, the ability to stimulate muscle stem cells to generate mature muscle cells could make a big difference in the lives of patients. By repairing muscles damaged by the disease, muscle regeneration therapy would extend the lives of patients and allow them to function effectively in a whole range of activities that are currently unthinkable for victims of the disease.

Recent work in Puri’s lab provides new insights into gene regulation—cellular mechanisms that control what proteins are produced in which types of cells. Their latest study, published online November 8 by The EMBO Journal, focuses on how the cues released within regenerating muscles instruct muscle stem cells that normally reside in muscle tissue to become mature muscle cells. In attacking these questions, the Puri lab has become interested in a protein called MyoD, which is known to turn on muscle-specific genes.

“Based on many precedents in biochemistry, we made the assumption that MyoD probably binds to other proteins in order to do its job,” explains Puri. “In this latest study, we screened a large collection of candidate binding partners and found one that caught our attention—a protein called BAF60c that unravels DNA, giving access to the cellular machinery that switches genes on.”

The team, led by Puri and Sonia Forcales, found that MyoD and its partner BAF60c sit on the correct part of the genome—the part where muscle-specific genes are located. But the researchers were puzzled when at first it looked like sitting there is all they do, without actually triggering the differentiation of stem cells into mature muscle cells.

Through the course of the study, Puri’s group came to find that the MyoD/BAF60c duo operate a bit like a surveyor. They mark the DNA of cells destined to become muscle cells and wait patiently for specific stimuli—such as exercise, injury, or disease—to signal additional proteins to join the complex on the genome. With this ensemble in place, the tightly wound genome is loosened, muscle DNA is fully exposed, and MyoD can begin reading the DNA and producing muscle-specific proteins.

This chain of events eventually triggers stem cell maturation into muscle cells, something the body needs to replenish diseased or damaged muscle tissue.

“What we’ve discovered here is the molecular mechanism by which muscles repair injury and or increase their size,” said Puri. “This is how muscles compensate for damage in the earlier stages of muscular dystrophy, but as the disease progresses, the system gets exhausted. We need to understand how this happens so we can figure out how to restore the process in muscular dystrophy patients.”

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Original paper:

Forcales SV, Albini S, Giordani L, Malecova B, Cignolo L, Chernov A, Coutinho P, Saccone V, Consalvi S, Williams R, Wang K, Wu Z, Baranovskaya S, Miller A, Dilworth FJ, & Puri PL (2011). Signal-dependent incorporation of MyoD-BAF60c into Brg1-based SWI/SNF chromatin-remodelling complex. The EMBO journal PMID: 22068056