A molecule called Jarid2 is responsible for balancing embryonic stem cells’ ability to turn into specialized cell types with the cellular chaos that could occur should they act too early, according to researchers at the Stanford University School of Medicine. Jarid2 recruits regulatory proteins to genes important in differentiation and also modulates their activity to keep them in a state of ongoing readiness.
“Understanding how only the relevant genes are targeted and remain poised for action is a hot topic in embryonic stem cell research,” says Joanna Wysocka, Ph.D., assistant professor of developmental biology and of chemical and systems biology. “Our results shed light on both these questions.” Dr. Wysocka is the lead author of the research, published in the December 24 issue of Cell in a paper titled “Jarid2/Jumonji Coordinates Control of PRC2 Enzymatic Activity and Target Gene Occupancy in Pluripotent Cells.”
Jarid2 had been previously identified as a protein important during development. Its role in embryonic stem cells, however, hadn't been addressed. The scientists found that Jarid2 works through a protein complex called PRC2 (polycomb repressive complex 2).
PRCs are known to keep genes quiet by modifying DNA-packaging proteins called histones. Specifically, PRC2 is necessary to regulate the expression of developmentally important genes in many types of cells. Dr. Wysocka and her colleagues further investigated how it works in embryonic stem cells.
When they looked in mouse embryonic stem cells, they found that nearly all PRC2 is bound to Jarid2, which is more prevalent in embryonic stem cells than in nonstem cells. The Stanford researchers found that together PRC2 and Jarid2 occupied specific stretches of histone-bound DNA in both mouse and human embryonic stem cells.
When they reduced the amount of Jarid2 in the cells, PRC2 was less able to bind the DNA and the cell began to churn out the proteins before they were needed. They believe that this confirms Jarid2's importance in stem cell differentiation.
Surprisingly, though, the degree of modifications on the histones remained about the same even when less PRC2 was bound to the DNA. “This was a crucial finding,” notes Dr. Wysocka, “because it shows that Jarid2 both recruits PRC2 to the DNA and modulates its ability to modify the histones.”
It also suggests that the Jarid2/PRC2 complex inhibits gene expression in other unidentified ways. Such fine-tuning of PRC2 activity, the researchers believe, allows the cell to carefully manage its degree of readiness for the subsequent unwrapping and expression of genes involved in differentiation of the embryonic stem cells into more specialized cells.
The researchers confirmed their findings in frog embryos, which are more easily studied at early stages of differentiation than are mouse embryos, by depleting Jarid2 expression. They found that embryos missing Jarid2 were unable to complete a critically important developmental step called gastrulation. “It was just as we would have predicted,” reports Dr. Wysocka. “Without Jarid2, which keeps the genes silent yet poised for activation, the embryos stop developing.”
The researchers now plan to further investigate the mechanism by which Jarid2 summons PRC2 to differentiation-specific genes in the stem cells and how it affects gene expression. The interaction may be important in human cancers as well. “PRC2 is upregulated in some cancers,” notes Dr. Wysocka, “which may help keep these cells in an undifferentiated, rapidly proliferating state. It will be interesting to see whether Jarid2 is also expressed at high levels in these diseases.”