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When X+X = X: Stanford scientists shed light on X-inactivation

2189014070_339cb830f9_z-1With apologies to some of my colleagues (cough, Margarita Gallardo, cough), I've never really enjoyed the Garfield comic strip. The rotund cartoon cat and his insatiable lasagna cravings has always seemed odd to me. Plus, most orange and black cats are female, due to a curious biological phenomenon called X inactivation.

The inactivation of one X chromosome in female animals (and humans) is necessary to ensure that both sexes end up with roughly the same dosage of X-chromosome associated genes. In most species, the chromosome to be inactivated is selected randomly in each cell early in development, and the selected chromosome remains inactive in all of the cell's subsequent progeny. Researchers believe that X inactivation might explain at least in part why some diseases are more prevalent or severe in one gender than the other.

Now dermatologist Howard Chang, MD, PhD, and former graduate student Ci Chu, PhD, have shed some light on the process, which occurs through the action of a regulatory RNA molecule called Xist. Their research was published today in Cell.

From our release:

[The researchers] have outlined the molecular steps of inactivation, showing that it occurs in an orderly and directed fashion as early embryonic cells begin to differentiate into more specialized tissues. They've identified more than 80 proteins in mouse cells that bind to Xist to help it do its job. They hope their findings will shed light on conditions in humans that are typically more severe in one gender than the other.

"We see some very interesting phenomena with X-linked diseases in humans," said [Chang]. "Often, when the faulty gene is on the X chromosome, the condition is more severe in boys. This happens in hemophilia, for example. In contrast, women are far more likely than men to suffer from autoimmune diseases, for reasons we don't yet understand. This research opens the door to possibly understanding the biological basis for these differences."

The researchers were able to pinpoint the protein partners of Xist only after Chu developed an entirely new technique. More from our release:

Chu's technique, which the researchers call CHIRP-MS for "comprehensive identification of RNA-binding proteins by mass spectrometry," allowed the researchers to identify the sequential interaction of over 80 proteins with Xist during X inactivation. Many of these proteins have never before been associated with that process. It's thought that they may help target and anchor Xist to active genes along the length of the X chromosome like burrs on a shoelace after a hike in the woods.

"If you lay all the copies of Xist in a cell end to end, they are not long enough to coat the entire X chromosome," said Chang. "Instead, Xist spreads judiciously, finding active genes and shutting them down. It also must stay anchored to the chromosome and not float over to any other chromosomes in the nucleus. This requires an elaborate set of machinery that we believe acts in a sequential fashion."

Specifically, the researchers suspect that some proteins help Xist locate and silence active genes, while others work to maintain that silencing once it has been established.

Clearly X inactivation is a complex process. But are you still wondering about Garfield? Because the genes for "orange" or "black" fur occur on the X chromosome, female cats that carry one of each version can be a patchwork of the two colors, depending on which chromosome is inactivated. Blobs of orange fur indicate an ancestor cell in which the chromosome with the black fur gene was inactivated, and vice versa. But a male cat, with only one X chromosome can only be orange or black, but not both.

An exception would be a male cat who had inherited two X chromosomes and one Y (in humans, this is called Klinefelter syndrome). This genetic anomaly, which is found in about one of every 3,000 calico cats, would likely have other oddities, however. Perhaps even a craving for pasta, cheese and tomato sauce?

Previously: Tomayto, tomahto: Separate genes exert control over differential male and female behaviors, Does it matter which parent your "brain genes" came from? and Stanford professor encourages researchers to take gender into account
Photo by Jerry Knight

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