How an RNA molecule attenuates the X chromosome


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In one of the mysteries behind mammalian evolution, each cell in the early female embryo shuts down one of its two copies of the X chromosome, leaving only one functional. For years, the mechanics behind this X chromosome inactivation have been murky, but researchers from Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA have now taken a major step forward in understanding the process.

Their findings, based on mouse stem cell research, change previous assumptions about how X-inactivation is initiated in female embryos and may lead to new ways of treating some genetic disorders, as well as a better understanding of how genes on other chromosomes are attenuated.

“X-inactivation is one of the most fundamentally important processes in evolution, and I think this study is a slam dunk in finally understanding it,” said Kathrin Plath, professor of biological chemistry and senior author of the paper, published in the journal Cell.

Because female cells have two X chromosomes and male cells have only one X and a Y, the inactivation process prevents females from receiving a double dose of X-related proteins. In some female cells, the X inherited from the mother is attenuated, while in others the X from the father is shut off – in a seemingly random way.

Researchers have known for almost three decades that an RNA molecule known as Xist is required for X chromosome inactivation early in embryonic development. They have also known that hundreds of other proteins interact with Xist. But in the absence of clear evidence, most in the field have erroneously assumed that many copies of Xist cover the targeted X chromosome or constantly move around between places on the X and interact directly with each of the more than 1,000 genes on the chromosome. to evoke their silence.

In the new study, Plath and her colleagues labeled individual molecules with fluorescence and used super-resolution microscopy to observe their exact locations on the chromosome. The team was then able to see Xist’s movements and dozens of interacting proteins while X chromosomes were inactivated in the embryonic stem cells from female mice. They discovered that pairs of Xist were located at only 50 spots along the chromosome, for a total of 100 molecules of Xist.

“It was a little shocking to us that Xist from just 50 sites manages to silence a thousand genes,” said UCLA associate project researcher Yolanda Markaki, first author of the paper.

Instead of interacting directly with each gene on the chromosome, Markaki and Plath showed that these Xist pairs act as hubs or protein magnets that recruit thousands of proteins to their spots on the chromosome. Then, specialized proteins pull the chromosome into a densely densified form so that each section is near one of these 50 large clouds of proteins. From there, gene-suppressing proteins in these complexes bind to each gene and shut it off.

“The key insight here is that Xist RNA does not act directly on the X chromosome, but is more of an architectural molecule that sets proteins up to do their job,” Plath said.

The team also identified the proteins, called Polycomb group proteins, that are responsible for twisting the X chromosome into the required shape. Without the Polycomb proteins, only those parts of the X chromosome that are already near one of the 50 Xist sites will be inactivated, the researchers found.

The results could help explain how molecules similar to Xist, called long non-coding RNAs or lncRNAs, interact with genes other than those on the X chromosome. Many lncRNAs are only present in very low numbers in cells, which has led researchers to wonder about their function.

“Now we know that to attenuate an entire chromosome, you only need 100 Xist molecules, so it’s easy to see how a few molecules are sufficient to set up small spaces of gene regulation,” Plath said.

The observations could also point to new ways of treating diseases, she said. For example, the reactivation of the attenuated X may serve as a strategy for the treatment of diseases associated with the X chromosome in women, such as Rett’s syndrome. Understanding how sound attenuation occurs opens the door to understanding how to reverse the process in differentiated cells if necessary.

Understanding X chromosome attenuation in humans

More information:
Yolanda Markaki et al., Xist nucleates local protein gradients to propagate silencing across the X chromosome, Cell (2021). DOI: 10.1016 / j.cell.2021.10.022

Journal information:

Provided by the University of California, Los Angeles

Citation: Xist marks the place: How an RNA molecule attenuates the X chromosome (2021, November 12) Retrieved November 13, 2021 from .html

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