The X chromosome creates a challenge for human cells. Unlike most chromosomes, which are present in duplicate regardless of a person’s sex, females have two copies of X while males have only one. Females don’t need twice as many of the genes encoded on the X chromosome as males, however, so they must inactivate one of their two copies.
How this inactivation occurs has been a long-standing question in cell biology — one Jeannie Lee’s lab at Mass General has been central to answering. In a study published last month, Lee and her colleagues describe how cells orchestrate this chromosomal silencing. The findings could lead to relief for the many thousands of people living with diseases caused by mutations on the X chromosome.
Inactivation depends on a gelatinous substance that coats all chromosomes, creating discrete bubbles that work as separators. “It’s like Jell-O. And if chromosomes weren’t surrounded by this Jell-O, they’d get tangled up like spaghetti,” says Lee, who is vice chair of the Department of Genetics at Harvard Medical School.
At the X chromosome, things get a bit more complicated. A gene on this chromosome instructs cells to make an RNA molecule called Xist (pronounced “exist”) that changes the material properties of the “Jell-O” around the X chromosome. When Xist first comes into contact with the Jell-O, the two engage in a tug-of-war, each pulling on the other. But Xist is no match for the Jell-O, and so it gets engulfed. Once inside, Xist changes the biophysical properties of the Jell-O, making it more flexible and closer to a liquid.
Other molecules important for X-chromosome inactivation also infiltrate the Jell-O. Together with Xist, these molecules work their way into nooks and crannies along the chromosome that would not be so accessible if the Jell-O were stiffer and thicker. By coating the X chromosome, they render it inactive. “It’s that simple!” Lee says.
But as simple as it sounds, figuring out how X-inactivation works has taken decades. At the end of this long journey lies a tantalizing possibility: Freeing inactivated X chromosomes could cure certain genetic disorders. That’s because mutations are often present on only one of two X chromosomes, but the healthy version of the gene is bound up in the inactivated chromosome, making it unavailable for cells to use.
The Lee lab has developed a number of approaches to unsilence X-linked genes in isolated cells, making them potential treatments for two such diseases: the intellectual disability Fragile X Syndrome and the neurodevelopmental disorder Rett Syndrome. “We’ll be further optimizing the approaches and doing safety studies over the next couple of years, and then we hope to move these compounds into clinical trials,” Lee says.
These treatments could also benefit males, even though their cells don’t use X-inactivation. A similar process silences individual genes on the X chromosome if they carry certain mutations, such as a mutation that causes Fragile X Syndrome.
Mysteries remain, however. For example, freeing inactivated X chromosomes seems to restore the function of mutated genes without having much impact on healthy genes carried by the chromosome. That’s encouraging because it suggests that this strategy can cure diseases with minimal side effects, but it’s not clear why other X chromosome genes remain largely unaffected. Lee thinks cells may have a limited capacity to use each gene, and that capacity is already maxed out by a single copy of a healthy gene. With mutated genes, on the other hand, the cell still has the capacity to use the healthy version when it becomes available.
Today, the clinical potential of Lee’s work is obvious, but that hasn’t always been the case. “We were supported by the National Institutes of Health for 25 years to answer a really basic question: How is the X-chromosome inactivated? And it’s only recently that we had this ‘Aha’ moment and realized we could get to a therapeutic,” she says.
The research described in this story received funding from the National Institutes of Health.
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