December 28, 2012
Study Looks At Stem Cell Maturity And Gene Expression
Connie K. Ho for redOrbit.com — Your Universe Online
Scientists from the Stowers Institute for Medical Research recently completed a study that shows the possibility that stem cells work towards maturity at an earlier stage than originally thought.
In particular, the researchers believe that embryonic stem cells are different from muscle or nerve cells in their ability to take on any cellular role. With this “pluripotency,” the stem cells are flexible enough to activate highly diverse gene expression programs to be turned into blood, brain, or kidney cells at any time. The results of the study were recently featured in the online edition of the journal Cell.
In the paper, the scientists explained how stem cells have a protein called Ell3 in portions of DNA, called “enhancers,” that necessitate activation of a neighboring gene. Ell3 is the third member of the Ell (eleven-nineteen lysine-rich leukemia gene) family of proteins that help elevate the rate of genes that are expressed. The study showed that Ell3 could help prepare a developmentally regulated gene for future expression along with the enhancer. The researchers believed that this particular finding is important as many of these genes are abnormally turned on in cancer.
“We now know that some enhancer misregulation is involved in the pathogenesis of solid and hematological malignances," commented Ali Shilatifard, an investigator at Stowers, in a statement. "But a problem in the field has been how to identify inactive or poised enhancer elements. Our discovery that Ell3 interacts with enhancers in ES cells gives us a hand-hold to identify and to study them."
A past study by a graduate student in the Shilatifard lab showed that Ell3 was related to over 5,000 enhancers. Many of these enhancers were in control of other genes that managed stem cell maturation in blood, kidney, and spinal cord cells.
"What was interesting was that Ell3 marked enhancers that are active and inactive, as well as enhancers that are known as "poised," explained Chengqi Lin, an Open University graduate student, in the statement.”That indicated that Ell3's major function might be to prime activation of genes that are just about to be expressed during development."
The current study showed how, with the correct developmental time, the Ell3 works with parts of the Super Elongation Complex, a major elongation factor, to release Pol II, a protein that initiates the copying of DNA into RNA blueprint. In the study, the researchers also found that mice stem cells that did not have many more Ell3 were not able to activate gene expression in mature cell types. They were able to find these results when they depleted mouse cells of Ell3 and then completed a “genomic” survey, discovering that Pol II disappeared from the start sites of a number of genes in Ell3-lacking genes. They found that the presence of Ell3 helped keep Pol II ready to work.
"It is very significant that Ell3 and other factors that regulate transcription are found in sperm," continued Lin, who is the study's first author, in the statement. “But it would be very exciting to further investigate whether transcription factors found in sperm could contribute to the decondensation of sperm chromatin or even further gene activation after fertilization by serving as epigenetic markers."
Overall, the researchers believe that the findings of the study have affected the study of Ell3 and Pol II.
"This work has opened up a whole new area of research in my lab," concluded Shilatifard in the statement. "If we find that transcription factors bind to specific regions of chromatin in germ cells, I may focus on germ cells in the next few decades. This would open a huge door enabling us to determine the role of these factors in early development."