An adult organism is full of different types of mature cells that perform very specific functions. Embryonic stem cells (ESCs) on the other hand, are ripe with potential; they are blank slates that have the ability to specialize into any type of cell in the body. As they begin to differentiate into a specific cell type, however, they no longer have that unlimited potential. Researchers have been trying to learn more about that process so they can create therapeutics that can regenerate damaged or diseased organs.
Salk Institute researchers have now found a protein complex called GBAF that stops stem cells from developing into specialized cells and allows them to maintain that unlimited potential. These findings, which have been reported in Nature Communications, may help scientists develop regenerative therapeutics.
"This project started as an exploration of embryonic stem cell pluripotency, which is this property that allows ESCs to become all different cell types in the body," said the senior author of the report Diana Hargreaves, an assistant professor in Salk's Molecular and Cell Biology Laboratory. "It's very important to know how various networks of genes control pluripotency, so finding a previously unknown protein complex that plays such an important regulatory role was very exciting."
ESCs are set upon their path to specialization when different genes are expressed. Large protein complexes called chromatin remodelers can change how DNA is organized, which impacts how genes are expressed. Hargreaves’ team was interested in how chromatin remodeler complexes come together and whether certain parts or subunits of the complex influence its function.
The researchers utilized a protein called BRD9; it's known to associate with a chromatin remodeler family called BAF, and may be one of BAF’s subunits. The team exposed dishes of ESCs to a chemical that inhibits BRD9 and then assessed the impacts on cell pluripotency - their ability to become any cell type.
The scientists showed that BRD9 puts the brakes on ESC development. With active BRD9, cells remain pluripotent. If BRD9 activity is inhibited, cells begin to specialize. Additional work indicated that BRD9 is a part of a BAF complex that has not yet been identified.
"For me, what was most exciting about our study was the fact that we had discovered a new BAF complex in embryonic stem cells," said the first author of the report Jovylyn Gatchalian, a Salk research associate.
"What we see with this work is that there's biochemical diversity at the level of individual variants of the BAF complex that allows for greater regulatory control,” added Hargreaves. “Understanding the complexities of that control is going to be key to any regenerative therapies."
Now, the researchers are planning to investigate how GBAF interacts with structural proteins that help organize the genome.