‘Chromosomal Jell-O’ may hold the answer to addressing genetic disorders associated with the X chromosome

The X chromosome presents a difficulty for human cells. Unlike the majority of chromosomes, which exist in pairs regardless of an individual’s sex, females possess two copies of X while males have merely one. However, females do not require double the genes encoded on the X chromosome as males do, necessitating the inactivation of one of their two copies.

The process of this inactivation has been a persistent inquiry in cell biology — one that Jeannie Lee’s laboratory at Mass General has played a pivotal role in addressing. In a study released last month, Lee and her team elaborate on how cells manage this chromosomal silencing. These revelations could provide relief for the countless individuals afflicted with disorders resulting from mutations on the X chromosome.

This inactivation relies on a gelatinous material that envelops all chromosomes, forming distinct bubbles that serve as separates. “It’s akin to Jell-O. If chromosomes weren’t encased in this Jell-O, they would entangle like spaghetti,” remarks Lee, who serves as vice chair of the Department of Genetics at Harvard Medical School.

Regarding the X chromosome, the scenario becomes more intricate. A gene on this chromosome instructs cells to produce an RNA molecule named Xist (pronounced “exist”) that alters the physical characteristics of the “Jell-O” surrounding the X chromosome. When Xist initially interacts with the Jell-O, both engage in a tug-of-war, each exerting force on the other. Yet, Xist cannot compete with the Jell-O, leading to its engulfment. Once engulfed, Xist modifies the biophysical attributes of the Jell-O, making it more pliable and resembling a liquid.

Additional molecules critical for X-chromosome inactivation also penetrate the Jell-O. Together with Xist, these components navigate through gaps and recesses along the chromosome that would be less accessible if the Jell-O were stiffer and thicker. By cloaking the X chromosome, they render it inactive. “It’s that straightforward!” says Lee.

Despite its apparent simplicity, unraveling the mechanisms of X-inactivation has spanned decades. At the conclusion of this extensive journey lies an enticing potential: Reactivating inactivated X chromosomes could alleviate certain genetic conditions. This is because mutations frequently exist on only one of the two X chromosomes, while the healthy gene is trapped in the inactivated chromosome, rendering it unusable for the cells.

The Lee lab has developed various methods to unsilence X-linked genes in isolated cells, which may become potential therapies for two such conditions: the intellectual disability Fragile X Syndrome and the neurodevelopmental disorder Rett Syndrome. “We will be further fine-tuning these methods and conducting safety evaluations in the upcoming years, and then we aspire to advance these compounds into clinical trials,” Lee adds.

These therapies could also assist males, despite their cells not utilizing X-inactivation. A similar mechanism silences specific genes on the X chromosome if they harbor certain mutations, like the mutation responsible for Fragile X Syndrome.

Nonetheless, enigmas persist. For instance, liberating inactivated X chromosomes appears to reinstate the function of mutated genes without significantly affecting healthy genes present on the chromosome. This is promising as it indicates that this approach can rectify diseases with minimal side effects, yet it remains unclear why other X chromosome genes remain relatively unaltered. Lee posits that cells may possess a limited capability to utilize each gene, and that capacity is likely maximized by a single copy of a healthy gene. In contrast, with mutated genes, the cell can still utilize the healthy variant when it becomes accessible.

Presently, the clinical implications of Lee’s research are unmistakable, though this has not always been true. “We received support from the National Institutes of Health for 25 years to resolve a fundamental question: How is the X chromosome inactivated? Only recently did we experience this ‘Aha’ moment and recognize that we could aim for a therapeutic solution,” she explains.

The research highlighted in this article was financed by the National Institutes of Health.