The addition of a chemical tag on an RNA molecule is the critical switch that inactivates one X chromosome in every cell, ensuring healthy development in all female mammals, WCM investigators say. The findings, published in Nature, could offer a new avenue to pursue treatments for X-linked chromosomal diseases such as Rett syndrome, in which a mutation causes neurons to make insufficient amounts of a protein needed for normal neurological development. All cells in female mammals contain two X chromosomes, but only one is needed for proper cell function and development. To ensure the proper expression level of genes on the X chromosome, one of the chromosomes is randomly inactivated in every cell. This occurs during embryonic development; once an X chromosome is inactivated, it stays inactive throughout the lifetime of the organism. The process of X chromosome inactivation is triggered by a type of RNA called XIST; the WCM investigators demonstrated that XIST is not solely empowered to turn off an X chromosome in every cell. Rather, XIST is activated once a chemical tag, called a methyl group, is added all along the length of the RNA. "Our study found that XIST is not functional until methyl groups are attached," says senior author Samie Jaffrey, M.D., Ph.D., professor of pharmacology. "These act as docking sites to recruit proteins that initiate a cascade of events leading to X chromosome inactivation."