Study broadens understanding of how cells regulate X chromosome inactivation

Published on November 28, 2012 at 4:12 AM · No Comments

In a paper published in the Nov. 21 issue of Cell, a team led by Mauro Calabrese, a postdoctoral fellow at the University of North Carolina in the lab of Terry Magnuson, chair of the department of genetics and member of the UNC Lineberger Comprehensive Cancer Center, broadens the understanding of how cells regulate silencing of the X chromosome in a process known as X-inactivation.

"This is a classic example of a basic research discovery. X-inactivation is a flagship model for understanding how non-coding RNAs orchestrate large-scale control of gene expression. In the simplest terms, we are trying to understand how cells regulate expression of their genes. Our findings are relevant across the board -- by understanding how normal cells function we can apply that knowledge to similar situations in the understanding and treatment of disease," said Calabrese.

Proper regulation of the X chromosome plays a crucial role in mammalian development. Females inherit a pair of X chromosomes from their parents, and the process of X-inactivation shuts down one of these two Xs.

"Males have XY. Females have two Xs. One of those Xs needs to get shut off. If it does not, it's not compatible with life. It's how we have evolved to equalize doses between males and females," said Calabrese.

While the manner in which the X chromosome is deactivated has been actively studied for 50 years, the exact mechanisms that regulate the process remain a mystery. Calabrese's research used high-throughput sequencing to determine the location and activity of chromosomes with far greater accuracy than previous research.

"Basically, this is using the sequencing technology as a high resolution microscope," said Calabrese.

Under a microscope, the inactive X chromosome (Xi) appears as a cloud-like structure, because it is covered with a non-coding RNA known as Xist. In the traditional model of X-inactivation, genes located inside the cloud are completely silenced, with 15 percent of the genes from the inactive X chromosomes escaping to become active.

"The prevailing thought was that genes that escaped X inactivation were pulled out of the core and expressed out there," said Calabrese.

The work of Calabrese's team complicates the current model of X-inactivation by finding indications of gene activity inside the Xist cloud and the presence of inactive genes outside the cloud, both of which would not have been thought possible in the prevailing model.

"It's kind of a subtle thing, but mechanistically it is a big difference," said Calabrese.

Inside the Xist cloud, sequencing discovered traces of DNase I sensitivity, a feature usually linked to transcription activity. While other markers associated with transcription were absent, the presence of DNase I sensitivity suggested that the nucleus did recognize the inactive X as usable DNA, but an unknown suppressive mechanism was preventing genes from being activated.

"We were surprised to see that. If they were totally silent, you would expect this to be not there- This suggests that transcription factors or other proteins that bind DNA are still accessing the inactive X," said Calabrese.

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