How Pioneer Factors Open DNA

Early on in each cell, the protein FoxA2 simultaneously binds to both DNA and the chromosomal proteins, opening the floodgates for gene activation, according to a new University of Pennsylvania study. The discovery, published Monday in Nature Genetics, helps untangle mysteries of how embryonic stem cells develop into organs.

Molecular signals begin dictating which organs an embryo’s stem cells will give rise to within the first two weeks of development. This process is guided by so-called “pioneer” transcription factors that gain access to the tightly packed DNA inside each cell so that other specialized proteins can get in and activate the necessary genes. However, until now, it has been unclear how these pioneer factors open the DNA.

“We now understand that this pioneer factor, FoxA2, grabs the chromosomal proteins, known as histones, and exposes the DNA region,” says senior author Kenneth S. Zaret. “That opening allows other specialized, regulatory proteins to access the DNA and activate a network of silent genes that leads to the formation of internal organs.”

Knowing how regulatory gene proteins work during this early stage can help the field better understand how to control the process of cell development for both clinical research and therapeutic purposes.

The researchers previously discovered pioneer factors in 2002 and have been working to better understand the role of these factors in early embryonic development. In this latest study, the team first used in vitro genetic techniques to investigate the interaction of FoxA with chromosomal proteins at the same time it interacts with DNA. They found that a small region of the FoxA2 protein was necessary for the protein to make an opening in the chromatin fiber.

Next, the teams translated those findings into a mouse model, deleting the same sequences in mice to see how those changes would affect embryonic development. Removing those key amino acid signatures significantly impaired embryonic development, caused deformities in organs—including the brain and the heart—and resulted in death in the mice.

“This very small deletion in the protein had a profound effect that mirrored what we had seen in vitro, which surprised us,” Zaret says. “We originally thought it would be a broadly acting phenomenon that would be hard to pinpoint, but we nailed it down.”

Zaret’s lab continues to investigate FoxA and other pioneer factors to learn how they may open up the chromatin and interact with chromosomal proteins.