Decoded: What ‘silences’ X chromosome in girls

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New York, Jan 11 (IANS) Nearly every girl and woman on Earth carries two X chromosomes in each of her cells — but one of them does (mostly) nothing. Do you know why?

That is because it has been silenced, keeping most of its DNA locked up and unread like a book in a cage, scientists led by an Indian-American researcher from the University of Michigan Medical School have revealed.

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

The findings could help lead to new ways of fighting diseases linked to X chromosomes in girls and women — the kind that occur when the X chromosome that does get read has misprints and defects.

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The team found that a known molecule called “Xist RNA” is insufficient to silence the X chromosome.

“Xist is widely believed to be both necessary and sufficient for X silencing,” said team leader Sundeep Kalantry.

“We, for the first time, show that it is not sufficient and 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 elaborated.

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, Kalantry added.

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

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It is this set of X-inactivation “escapees” that the research team was 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.

According to Kalantry, it is this higher “dose” in females that triggers X-inactivation selectively in females; the lower dose in males is insufficient.

“That means that if researchers can determine exactly which factors cause X-inactivation to occur, they could find ways to affect the activity of genes on the X chromosomes – specifically, genes involved in certain diseases.” the authors noted.

Many of them have an impact on an individual’s thinking and memory capacity, and other aspects of cognition and intelligence.

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“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 so-called escapee genes and ameliorating the effects of the unhealthy copy,” Kalantry explained.

Unfortunately, this approach probably won’t help males with X-linked diseases, because they only have a single X chromosome in each cell and inactivating it would be harmful.

The new paper appeared in the journal Proceedings of the National Academy of Sciences.

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