New Discovery on X Chromosome Inactivation May Open Treatment Avenues for Rett Syndrome
Researchers have discovered that early inactivation of the X chromosome is a two-step process regulated by two different genetic structures, a finding that may open up new possibilities for the treatment of X-related diseases, such as Rett syndrome.
The study, “Xist Repeats A and B Account for Two Distinct Phases of X Inactivation Establishment,” was published in the journal Developmental Cell.
Due to a process known as X chromosome inactivation (XCI), genes are turned “on” only from one of the two chromosomes that mammalian females, including humans, have.
Once one of the X chromosomes is selected to be “silenced,” an RNA molecule — called Xist — initiates the gene silencing process. But Xist does not act alone, recruiting proteins called Polycomb repressive complexes (PRC) 1 and 2 to completely inactivate the selected X chromosome.
The silencing process occurs in two phases: establishment and maintenance. In the last stage, inactivation becomes stable and is harder to be reversed.
Rett syndrome, a disorder that almost exclusively affects girls, is caused by mutations in the MECP2 gene, located in the X chromosome. The gene provides instructions to make the MeCP2 protein, responsible for maintaining synapses, which are the junctions where nerve cells communicate.
A potential way to treat Rett syndrome and other X-chromosome-linked disorders is to devise a strategy to reactivate the healthy copy of the MECP2 gene in the inactive X chromosome.
“Why don’t we put the dormant X chromosome to work and rescue the cells that are lacking a proper copy of MECP2?” asks Jeannie Lee, PhD, the study’s senior author, in a press release.
Previous research has shown that two particular Xist structures, called repeat A and B, are responsible for recruiting the Polycomb complexes.
However, the role played by each repeat remains controversial. While some studies indicated that repeat A was crucial to recruit Polycomb, others argued that repeat B was solely responsible.
Using embryonic stem cells from a female mouse, they studied what happened when repeat B was removed from the Xist gene. The scientists observed that although cells could initiate the silencing within eight days, the process could not be maintained. Cells lacking repeat B were still able to recruit Polycomb to some extent, yet this lowered over time.
When researchers removed repeat A, they found that only 9% of cells carried both X chromosomes at day 14, indicating that one X chromosome needs to be silenced so that cells survive without repeat A. At this point, the researchers also observed that genes such as Mecp2 — the mouse version of MECP2 — failed to be silenced.
Further experiments suggested that repeat A is key to promote correct localization and spreading of Xist, and also to start Polycomb recruitment. After this phase, repeat A seems to be indispensable, and repeat B becomes responsible for stabilizing Polycomb during XCI establishment.
Overall, “our study reveals establishment of gene silencing and Polycomb domains to be more complex than previously thought,” the researchers wrote.
“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,” Lee said.