A gene crucial to maintaining embryonic stem cells' all-purpose, pluripotent state has been identified by scientists at the University of California, San Francisco.
The researchers say that their finding may prove helpful in improving the scientific understanding of how cells acquire their specialized states, and provide a strategy to efficiently reprogram mature cells back into the pluripotent state, an elusive step in stem cell research but one crucial to a range of potential clinical treatments.
AdvertisementThey conducted their research on mouse embryo cells, and found that a gene known as Chd1 loosens the packaging that normally protects DNA in the cell nucleus.
The research group say that this step, known as chromatin remodelling, allows the cell's protein-making machinery to gain access to the DNA, and transform progenitor cells into specialized cells and tissue, such as neurons, muscle and bone.
A number of genes are known to trigger chromatin remodelling, allowing small sections of DNA to become accessible in order to make specific proteins.
The scientists say that Chd1 is the first gene found to regulate a "global" loosening of the DNA in embryonic stem cells. The global condition sets the stage for turning on many different genes to make a broad range of specialized cells.
"Embryonic stem cells are characterized by this open state, but, up to now, we didn't know the mechanisms that maintain this state, or even if it is necessary for the full stem cell potential," Nature magazine quoted Alexandre Gaspar-Maia, lead author of the paper, as saying.
"We found that Chd1 is critical for both, and for allowing an efficient reprogramming. Chd1 is important for allowing the normal differentiation process, and it is essential for playing the 'differentiation tape' backwards - bringing differentiated cells back to pluripotency," he added.
The scientists discovered the pivotal role of Chd1 by using the powerful technique of RNA interference (RNAi) to screen this gene, and 40 other candidate genes.
When the researchers silenced the gene by using the technique, embryonic stem cells could not make the full range of specialized cells.
In a laboratory test used to simulate normal cell specialization, the scientists detected no differentiation of cardiac muscle, and also no formation of a tissue known as primitive endoderm, which is essential for the embryo to survive and develop.
The researchers also found Chd1 to be necessary for the reprogramming of specialized cells back to the pluripotent stem cell state.
They are planning to further study chromatin remodelling in more detail to clarify what other molecules work in concert with the Chd1 gene to direct the process, hoping that this would aid efforts to increase the efficiency and safety of reprogramming cells.
According to them, their research may also shed light on how cells transition from one type to another, a process that happens normally during embryonic development and goes astray in cancer.
"We now know that Chd1 is essential, and, so far, appears unique in its global effect, but we expect that there are major players yet to be discovered," said senior author Ramalho-Santos, UCSF assistant professor of obstetrics, gynecology and reproductive sciences, and pathology.
"If we can understand how Chd1 works, that will also tell us more about how the cells regulate their precise specialization during development, and turn on their pluripotency program during reprogramming," Ramalho-Santos added.
Based on their findings, the researchers came to the conclusion that embryonic stem cells exist in a dynamic state, poised between the open condition that may assure the cell's full potential, and the more constrained state that allows only certain kinds of cells to progress.
Chd1, they say, is central to maintaining the open, pluripotent stem cell state.