UNC study pinpoints gene crucial for female embryo survival
Gene keeps paternal X chromosome inactive
CHAPEL HILL - A gene discovered by scientists at the University of North Carolina at Chapel Hill appears to be crucial for female embryo survival.
A study authored by UNC researchers and published in the August issue of "Nature Genetics" furthers the understanding of a fundamental biological process in mammals and contributes important new knowledge to gene regulation in the developing embryo. It also has implications for problems such as fetal loss, tumor development, birth defects and mental retardation.
The report notes that the gene, eed, when functioning normally in female mouse embryos, keeps the paternal X chromosome inactive and many of its genes shut down in early placental cells. In the new research, female embryos without a functioning eed do not survive because of problems in forming placentas.
Other studies have shown that the gene Xist is responsible for putting the molecular brakes only on the X chromosome. As female mammals have two X chromosomes (XX) and males an X and Y (XY), imbalance occurs because female embryos have twice as many X-linked genes.
That's where Xist comes into play. It gets turned on early in the development of the female embryo. This gene is activated from the X chromosome that's going to be shut down, which in early placental material is only the X from the father, according to Terry Magnuson, PhD, senior author of the new study and Kenan professor of genetics at UNC-CH School of Medicine.
"Once the paternal X chromosome is shut down, then the cells must continue to divide and keep it shut down. Until now, it's not been understood what maintains this X in an inactivated state. Now we know that eed plays a role in this process," said Magnuson.
"Without eed functioning normally, the father's X chromosome is shut down and then it comes back on. When that happens, too many X chromosome genes are active, there are problems forming placental tissue, and female embryos die."
Magnuson pointed out that X inactivation also occurs within the embryo itself, not just in early placental (trophoblast) material surrounding the embryo. However, this occurs randomly since about 50 percent of the time either the paternal or a maternal X chromosome is shut down.
The new findings also suggest that eed may be critical in a fundamental process known as imprinting, a phenomenon in which a specific gene is expressed, or turned on, depending on whether it is inherited from the mother or the father.
"We know that this gene [eed] does other things as well. It's involved in tumor genesis. If the gene is mutated in a way that is less severe, where the protein is still produced and still functions but not to optimal efficiency, then the animals come to term and are susceptible to developing leukemias. They also have skeletal and other problems." Magnuson said.
"This gene is also involved in telling cells where to go in the embryo - to make head versus tail versus gut. Without this gene functioning in the proper way, those cells move to the wrong place. And that can result in birth defects.
"We've learned from the human genome projects that there are far fewer genes than were originally estimated, roughly 35,000. In a complex organism like humans, those 35,000 genes must act in concert with one another in many different combinations at many different times," Magnuson said.
"So understanding how genes are regulated in terms of their expression, how they are turned on and off, and if they are off how they are maintained in that 'off' state, becomes critical in the post-genome era of understanding gene function."
Magnuson's principal co-authors are Jianbo Wang, PhD and graduate student Jesse Mager. Other UNC authors from the department of genetics are postdoctoral fellow Yijing Chen, PhD and research assistant Elizabeth Schneider. Other study co-authors are James C. Cross, PhD of the University of Calgary, Alberta, Canada and Andras Nagy, PhD, of the Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Canada.
The study was funded by a grant from the National Institute of Child Health and Human Development. UNC-CH has committed at least $245 million over the next decade to the emerging field of genome sciences. The campuswide initiative, headed by Magnuson and which represents public and private investments, will allow Carolina to be a driving force in determining how the genomics revolution will change the way we treat human diseases, design drugs and grow crops. This collaborative effort includes construction of four new buildings to house genomics research, more than $50 million in recurring funds for 40 new faculty positions and a $25 million anonymous gift to create the Michael Hooker Center for Proteomics to study a specialized area of genetics. For more information on the genome sciences initiative, go to www.unc.edu/genome.
University of North Carolina School of Medicine. July 2001.
rating: 0.00 from 0 votes | updated on: 26 Jun 2007 | views: 1232 |