For many years, scientists thought they understood the inactivity of X chromosomes in females. However, new University research challenges previous assumptions and could lead to new avenues for treating diseases tied to the chromosome.

Females have two X chromosomes, while men have one X chromosome and one Y chromosome. As a result, one of the X chromosomes in women is randomly inactivated in order to balance gene expression. Chromosomes contain DNA, the instructions for how the body functions.

In a paper recently published in the Proceedings of the National Academy of Sciences, University researchers from the Department of Human Genetics suggest that a molecule called Xist RNA, which was previously understood to be responsible for making one of the X chromosomes inactive, is actually insufficient in doing so on its own.

Instead, according to the research, there have to be other molecules exist on the X chromosome that interact with Xist to inactivate the chromosome.

Human Genetics Prof. Sundeep Kalantry, who headed the project, said to conduct the study researchers engineered male cells to express Xist RNA, which they normally don’t do.

“Xist is normally only expressed in female cells from the inactive X chromosome,” Kalantry said. “When we took away an RNA transcribed in the opposite direction too, we got male cells to express Xist. We saw that these male cells expressing Xist do not undergo X chromosome inactivation, so this allowed us to conclude that Xist is insufficient to cause inactivation.”

Once researchers found that Xist RNA does not by itself cause X chromosome inactivation, they were able to move toward a better understanding of what else is needed for the process to occur. The answer ultimately pointed toward other molecules in the cell.

“We found that female cells have other factors on the X chromosome itself that male cells don’t, and these factors are the master regulators of X inactivation,” Kalantry said.

Implications of finding those factors are far ranging, he added.

“If you were to increase or decrease the levels of these regulators, then you can turn on or off particular genes on the X chromosome that normally would not be turned on or off,” Kalantry said. “As a result, you can modulate X-linked gene expression.”

Controlling X-linked gene expression — the appearance of certain characteristics or illnesses tied specifically to the X chromosome — permits researchers to be better able to understand how X chromosome inactivation occurs.

Postdoctoral fellow Srimonta Gayen said this understanding could then have therapeutic applications, by allowing scientists to activate the healthy parts of the silenced X chromosome to compensate for disease-causing aspects within the originally activated chromosome. This type of activation has previously not been possible.

Diseases linked to the X chromosome include autism, hemophilia and muscular dystrophy.

“If we increase understanding of the mechanism of how X-linked chromosome inactivation actually occurs, we can better understand X-linked chromosomal diseases,” Gayen said.

The study’s authors said future research aims to further investigate the regulating factors this study suggested were responsible for X chromosome inactivation.

“We want to find these other factors,” Kalantry said. “We already have one of them worked out, and this is close to being published.”

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