Spotlight on Neurogenetics

Sundeep Kalantry
Assistant Professor
Ph.D., Weill Graduate School of Medical Sciences
of Cornell University

The X factor

Consider the tortoiseshell cat. Its patchwork of fur colors is not only a delight to feline fanciers, it's also a classic example of a biological phenomenon known as X-chromosome inactivation.

Seen almost exclusively in female cats, the tortoiseshell coat color pattern results from the silencing of one or the other of the two X-chromosomes that female mammals carry (males have one X and one Y). In orange patches, the X-chromosome that bears the black version of the coat-color gene is silenced; in black patches, the X with the orange version is inactivated.

The genome, biology textbooks tell us, is the blueprint for the human body and the master instruction book for the myriad processes that occur within it. But the genes themselves need rules for when and where to be active. These instructions -- the epigenome -- are found not in the genetic code but in controllers that lie along the length of the DNA double helix and posses the awesome power to turn genes on and off.

"All the cells in the body have the same DNA, but different sets of genes are active and inactive in different cells and tissues – heart, kidney, liver, for example," explains Kalantry. "A central question is, how does the cell know to keep only the genes that are necessary in the kidney turned on in the kidney? We're now beginning to appreciate that much of this is due to epigenetic processes."

Unlike genetic mutations, which are permanent, epigenetic changes can be reversed, says Kalantry. "So as a cell's environment changes, the cell's gene expression profiles can change accordingly, often through its epigenetic machinery."

The potential connections to disease are obvious. "An error in just one component of the epigenetic machinery can cause changes in the expression of many genes and bring about huge changes in cell behavior. So changes in this machinery are a powerful way to affect the health of the cell," says Kalantry, whose fascination with heredity and genetic disorders began in high school while he worked in a lab at the NYU School of Medicine. (His work there led to a semi-finalist award in the annual Westinghouse Science Talent Search, a nationwide research competition for high school seniors.)

Because many of the molecules that silence genes on the X-chromosome also silence genes on other chromosomes, X- inactivation is a powerful system for understanding gene regulation throughout the genome. In Kalantry's lab, the search is on for epigenetic molecules that directly trigger that silencing in a special type of X-inactivation called imprinted X-inactivation.

One suspect was Xist (pronounced "exist"), a type of RNA that performs none of the usual RNA tasks involved in protein production, but has another job in X-inactivation.

Xist is expressed from only one of the two X-chromosomes – the one that will become inactivated – and appears to remain attached to the chromosome, tagging it as the one to be silenced. Xist, however, is not absolutely necessary to trigger chromosome-wide inactivation, Kalantry's group discovered. Neither are members of an infamous gang of proteins called the Polycomb group, which are known to misbehave in certain cancers, potentially by silencing genes that would otherwise be active. However, both Xist and Polycomb proteins appear to "solidify" the inactive state, rather than initiate it, Kalantry says.

Another molecule, recently discovered by Kalantry's group and dubbed MTase-Xi, does appear to be required for imprinted X-inactivation. Experiments are underway to learn more about how it works.

"If MTase-Xi does what we think it does, " Kalantry says, "then it holds enormous promise as a molecule that, by its mere presence or absence, mediates a change in which set of genes is turned on or off. "