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Press ReleaseJun | 11 | 2020
BOSTON—Researchers at Massachusetts General Hospital have identified a key mechanism in X chromosome inactivation, a phenomenon that may hold clues that lead to treatments for certain rare congenital disorders. Their findings, published in the journal Developmental Cell on June 11, 2020, may also aid in the creation of novel medicines for certain cancers.
Female humans and other mammals have two copies of the X chromosome in each of their cells. Both X chromosomes contain many genes, so only one of the pair can be active; having both X chromosomes expressing genes would be toxic to the cell. For this reason, female mammals developed a mechanism called X chromosome inactivation, which silences one chromosome, explains Jeannie Lee, MD, PhD, of the Department of Molecular Biology at Mass General, senior author of the Developmental Cell study.
Jeannie Lee, MD, PhDWe think that through interfering with the Xist recruitment of Polycomb and other silencing complexes, we may eventually be able to treat X-linked diseases like Rett syndrome and perhaps even cancer.
The goal of X chromosome reactivation has led scientists to focus on epigenetic factors, which turn genes “on” or “off” without altering the genetic code. Silencing genes on the X chromosome occurs when a form of noncoding RNA called Xist spreads across the X chromosome, explains Lee. However, Xist doesn’t act alone: It must attract proteins called Polycomb repressive complexes (PRC) 1 and 2 to complete inactivation of the X chromosome.
But how Xist pulls in PRC1 and PRC2 had been unclear and the subject of debate. Research indicates that repeating sequences of nucleotides on Xist called Repeat A and Repeat B appear to act as magnets for these proteins. Yet some recent research suggests that Repeat A plays no role.
Understanding how Xist “recruits” PRC1 and PRC2 could have far-reaching implications, especially since the latter plays a key role in maintaining overall cell health. “We think that through interfering with the Xist recruitment of Polycomb and other silencing complexes, we may eventually be able to treat X-linked diseases like Rett syndrome and perhaps even cancer,” says Lee.
Jeannie Lee, MD, PhD, of the Department of Molecular Biology at Mass General, is also director of the Lee Laboratory and a professor of Genetics at Harvard Medical School. The lead authors of the Developmental Cell paper were David Colognori, PhD, a postdoctoral scholar at the UC Berkley/California Institute for Quantitative Biosciences, and Hongjae Sunwoo, PhD, a senior scientist at Intellia Therapeutics.
Paper cited: Colognori D, Sunwoo H, Wang D, Wang CY, Lee JT Xist Repeats A and B Account for Two Distinct Phases of X Inactivation Establishment Developmental Cell 2020 Jun 11.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1B and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2019, Mass General was once again named #2 in the U.S. News & World Report list of "America’s Best Hospitals."
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