New mechanism shows promise for treating certain congenital disorders

Scientists from Massachusetts General Hospital have discovered a major mechanism in the inactivation of X chromosomes, an event that may hold clues to develop new treatments for specific rare congenital disorders.

Published in the Developmental Cell journal on June 11^th, 2020, the findings may also assist in the development of new medicines for specific kinds of cancers.

Many mammals, including female humans, have two copies of the X chromosome in each of their cells. The two X chromosomes comprise several genes, which means only one of the pair can be active; the presence of both X chromosomes expressing genes would be harmful to the cell.

Consequently, female mammals developed a mechanism known as X chromosome inactivation, which silences only one chromosome, explained Jeannie Lee, MD, PhD, from the Department of Molecular Biology at Massachusetts General Hospital and senior author of the study.

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.”

Jeannie Lee, MD, PhD, Study Senior Author, Department of Molecular Biology, Massachusetts General Hospital

Understanding how to inactivate and reactivate an X chromosome would have significant implications for medicine. A prominent category of beneficiaries could be individuals with specific congenital diseases called X-linked disorders, which are induced by mutations in genes on the X chromosome.

One case of point is Rett syndrome, a disorder caused by a mutation in a gene known as MECP2 that nearly always appears in girls and leads to profound issues with coordination, language, learning, and other functions of the brain. Theoretically, a medical disorder like Rett syndrome could be treated by reactivating the X chromosome.

Lee asked, “Why don’t we put the dormant X chromosome to work and rescue the cells that are lacking a proper copy of MECP2?”

The aim of X chromosome reactivation has directed researchers to target epigenetic factors, which switches genes “on” or “off” without modifying the genetic code. On the X chromosome, silencing genes appear when a form of noncoding RNA known as Xist spreads across the X chromosome, Lee explained.

But Xist does not perform alone: it must attract proteins known as Polycomb repressive complexes (PRC) 1 and 2 to finish the inactivation of the X chromosome.

But it is not clear how Xist pulls in PRC1 and PRC2, and this has been a topic of intense debate. Studies show that repeating sequences of nucleotides on Xist known as Repeat A and Repeat B appear to serve as magnets for these kinds of proteins. However, some latest research indicates that Repeat A does not play any role.

Study details

In the recent study, Lee with her collaborators demonstrated that both Repeat A and Repeat B are required to attract PRC1 and PRC2 and complete the inactivation of X chromosomes. When the researchers deleted Repeat A from Xist in mouse embryonic stem cells, they observed that the inactivation of X chromosomes is not only foiled but one X chromosome is also eliminated completely for the cells to endure in culture.

When one X chromosome is missing in human females, this leads to Turner syndrome, which affects fertility, stature, and other physical traits.

Leaning how PRC1 and PRC2 are “recruited” by Xist may have far-reaching implications, particularly because the former has a major role in maintaining the overall health of the cells.

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.”

Jeannie Lee, MD, PhD, Study Senior Author, Department of Molecular Biology, Massachusetts General Hospital