Scientists of the Center for Regenerative Medicine and Studies of Stem Cells Eli and Edith Rod, at the University of California in Los Angeles, revealed the mechanism of inactivating the second copy of the X-chromosome in women who remained a mystery for many years. The opening is reported in the article published in the Cell magazine.
The mammalian females have two x-chromosomes, that is, two sets of genuine genes. Since only one X chromosome is present in males cells, a situation arises with unevenness of gene expression levels, which can lead to various anomalies. So that this does not happen, there is a dose compensation mechanism, when one x-chromosome in females is completely suppressed. Until now, scientists do not know how the inactivation is happening, however, it is known that the choice of one of the two chromosomes is carried out randomly and an important role in this is played by the XIST molecule.
xist is necessary for inactivating the X-chromosome in the early stages of embryonic development, while it interacts with hundreds of other proteins. The researchers assumed that either a set of XIST copies completely cover the target chromosome, or RNA molecules move from the gene to the gene, directly forcing them to “silence”. To test these hypotheses, scientists marked separate RNA molecules with fluorescent tags and used microscopy of ultra-high resolution to determine their exact location on the chromosome.
It turned out that the XIST is located just 50 points of the X-chromosome, which is enough to turn off (silencing) more than a thousand genes. RNA molecules attract a set of specialized proteins to chromosome. When DNA is tightly packed as a result of other proteins (Polycomb groups), all X-chromosome genes are in the immediate vicinity of silenets. When researchers suppressed Polycomb group proteins, only those sections of the X chromosome were inactivated, which were near the XIST points.
Results will help develop new methods for the treatment of diseases associated with dose compensation. For example, the reactivation of the X-chromosome can serve as a strategy for treating diseases such as Rett syndrome, which is expressed in severe mental backwardness and is associated with the mutation of the Mesarian gene in X-chromosome.