What ''silences'' X chromosome in girls decoded

Washington

Scientists led by an Indian-origin researcher may have discovered what actually silences the X chromosome in girls, a finding that could lead to ways to counteract X-linked diseases in women.

Nearly every girl and woman on Earth carries two X chromosomes in nearly every one of her cells — but one of them does mostly nothing.

That is because it has been silenced, keeping most of its DNA locked up and unread like a book in a cage. Scientists thought they had figured out how cells do this, but new findings by researchers at University of Michigan Medical School in US shows the answer is not quite that clear.

Researchers show that a molecule called Xist RNA is insufficient to silence the X chromosome. The gene for that molecule, Xist, has been seen as the key factor in silencing one of the two X chromosomes in every female cell.

"Xist is widely believed to be both necessary and sufficient for X silencing," said Sundeep Kalantry, assistant professor of human genetics who led the study.

"We for the first time show that it is not sufficient, that there have to be other factors, on the X-chromosome itself, that activate Xist and then cooperate with Xist RNA to silence the X-chromosome," he added.

According to researchers, in the future it may be possible to change the level of these other factors in cells and turn on the healthy, silenced copy of a gene that lies on the inactive X-chromosome.

The Xist gene, short for X-inactive specific transcript, is found on each X chromosome. It does not tell cells to produce a protein, like most genes do.

Instead, it produces Xist RNA that physically coats the entire X-chromosome, and thereby is thought to seal most of it off from the rest of the cellular world.

Now, the researchers have shown that Xist has to have accomplices. They reside in the X chromosome that is destined to get silenced.

Although most genes on the inactive X chromosome are fully silenced, a handful of the genes on the inactive X are in fact active.

It is this set of X-inactivation 'escapees' that the researchers focused on.

Since the 'escapee' genes are expressed from both the active and the inactive X-chromosomes in females, they produce more gene product in female cells than in male cells, which only have a single X.

The researchers predict that it is this higher 'dose' in females that triggers X-inactivation selectively in females; the lower dose in males is insufficient.

A wide range of relatively rare diseases — as well as relatively common conditions such as autism, hemophilia and muscular dystrophy — are linked to problems with genes found on the X chromosome.

"In females, we could envision 'reawakening' a healthy copy of an X-linked gene on the inactive X chromosome, by modulating the dose of these escapee genes and ameliorating the effects of the unhealthy copy," said Kalantry.

The study was published in the journal PNAS. — PTI