By Deborah Oakley
Scientists can now predict which genes may be easiest to turn on inside a woman’s cells. These genes, and the entire X chromosome on which they sit, are usually inactive. Turning specific genes back on could one day help to treat certain diseases of the X chromosome.
“Our findings offer a fundamental insight into how genes are inactivated, in a process called epigenetics. This is an important first step in developing a way to re-activate specific genes to treat diseases that primarily affect women, such as the rare brain disorder Rett’s Syndrome,” says Irene Cantone, of the MRC London Institute of Medical Sciences (LMS) and who played a key role in the research, published in Genome Biology.
The genes inside our cells are stored in two structures called chromosomes. There are two special chromosomes, called X and Y, which carry the information that determines sex. Every cell has two of these chromosomes. Males have one X and one Y, whilst females have two Xs. Female cells only need to use one X, because using both would mean an extra set of genes would be active. To avoid this, one chromosome is randomly turned off in favour of the other.
It has been known that some genes can escape inactivation. This study shows that the escape is not completely random, but instead the genes which escape most often are in some way predisposed to do so.
The LMS team looked at the activity of genes on the inactivated X chromosome in individual cells. They found that genes on this chromosome which can escape inactivation do so in a subset of the cells that make up a tissue. This diversity between cells has been missed in previous studies that looked at average gene activity across whole tissues.
By looking in closer detail, the LMS researchers found that the chance of a given gene escaping inactivation on can be predicted by its position on the chromosome. This predictive power may allow scientists to target these genes and turn them back on systematically, in every cell within a tissue, to try to treat diseases of the X chromosome.
Disease can occur when a gene on the active X chromosome is mutated and malfunctions. Re-activating the same version of the gene on the inactive chromosome could be an elegant way to treat the illness. Before scientists can do this, they first need to understand how genes are inactivated, but it’s difficult to observe in human cells.
Last year, Cantone and colleagues developed a new and advanced technique that allows them to watch what happens in human cells for the first time. They do not watch inactivation directly, but instead reverse the process, reactivating an inactive X chromosome. By watching which genes are turned back on first, and how the process unfolds, they can learn how inactivation might happen naturally inside our cells. One day, this may allow them to direct this process.
The LMS team has used the technique to identify which genes are the first to be turned back on during re-activation. Their findings were published in Nature Communications in August last year. Now they have built on these results, showing that some genes in the cells of connective tissue may be turned back on naturally during the course of a woman’s life. These genes have a predisposition to being re-activated, says Cantone, and may hold the most potential as targets in treating diseases of the X chromosome.
“We’re starting to unravel what it takes to reactivate genes. And we know that, hypothetically, if we reactivate the normal copy of the gene, we cure the disease,” says Cantone. “Next we need to understand how to turn the gene back on. In the future it may be possible to achieve the targeted reactivation of a chromosome, perhaps with a combination of different drugs.”
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