Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Research reveals new understanding of X chromosome inactivation

27.11.2012
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.

The other surprising findings involve the 15 percent of “escaper” genes from the inactive X. Calabrese found evidence that active genes were found both inside and outside the Xist cloud, and that silenced genes that lay alongside active genes outside of the Xist cloud remained inactive.

“If X-inactivation was a strict nuclear barrier, then pulling a gene outside the barrier would turn it on, but it has got to be more than that because when an inactivated gene that is beside an escaper is outside this domain, it is still turned off,” said Calabrese.

The presence of DNase I sensitivity within the Xist cloud and the finding of inactive genes outside of the cloud suggest that a site-specific mechanism is regulating genes on the chromosome in a more subtle way than the binary “on/off” function posited by the prevailing model. The exact mechanism for this remains unknown. Although Calabrese believes that Xist still plays a role, its exact function and whether other factors influence X-inactivation remain questions for future research.

“We know that Xist is required to turn off the inactive X. We know that. We have no idea how” said Calabrese.

Beyond revising the understanding of how X-inactivation works, Calabrese said that deeper understanding of the function of Xist could reveal more about the role of other non-coding RNAs in cellular development. These RNAs could become useful targets for future therapies and drug development.

“We know that too much expression of the wrong non-coding RNAs can lead to cancer. Also, forced expression of other non-coding RNAs can prevent cancer. Generally, we do not know how these RNAs work,” said Calabrese.

William Davis | EurekAlert!
Further information:
http://www.unc.edu

Further reports about: DNA DNase X chromosome X-inactivation non-coding RNAs transcription factor

More articles from Life Sciences:

nachricht MACC1 Gene Is an Independent Prognostic Biomarker for Survival in Klatskin Tumor Patients
31.08.2015 | Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft

nachricht Fish Oil-Diet Benefits May be Mediated by Gut Microbes
28.08.2015 | University of Gothenburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: An engineered surface unsticks sticky water droplets

The leaves of the lotus flower, and other natural surfaces that repel water and dirt, have been the model for many types of engineered liquid-repelling surfaces. As slippery as these surfaces are, however, tiny water droplets still stick to them. Now, Penn State researchers have developed nano/micro-textured, highly slippery surfaces able to outperform these naturally inspired coatings, particularly when the water is a vapor or tiny droplets.

Enhancing the mobility of liquid droplets on rough surfaces could improve condensation heat transfer for power-plant heat exchangers, create more efficient...

Im Focus: Increasingly severe disturbances weaken world's temperate forests

Longer, more severe, and hotter droughts and a myriad of other threats, including diseases and more extensive and severe wildfires, are threatening to transform some of the world's temperate forests, a new study published in Science has found. Without informed management, some forests could convert to shrublands or grasslands within the coming decades.

"While we have been trying to manage for resilience of 20th century conditions, we realize now that we must prepare for transformations and attempt to ease...

Im Focus: OU astrophysicist and collaborators find supermassive black holes in quasar nearest Earth

A University of Oklahoma astrophysicist and his Chinese collaborator have found two supermassive black holes in Markarian 231, the nearest quasar to Earth, using observations from NASA's Hubble Space Telescope.

The discovery of two supermassive black holes--one larger one and a second, smaller one--are evidence of a binary black hole and suggests that supermassive...

Im Focus: What would a tsunami in the Mediterranean look like?

A team of European researchers have developed a model to simulate the impact of tsunamis generated by earthquakes and applied it to the Eastern Mediterranean. The results show how tsunami waves could hit and inundate coastal areas in southern Italy and Greece. The study is published today (27 August) in Ocean Science, an open access journal of the European Geosciences Union (EGU).

Though not as frequent as in the Pacific and Indian oceans, tsunamis also occur in the Mediterranean, mainly due to earthquakes generated when the African...

Im Focus: Self-healing landscape: landslides after earthquake

In mountainous regions earthquakes often cause strong landslides, which can be exacerbated by heavy rain. However, after an initial increase, the frequency of these mass wasting events, often enormous and dangerous, declines, in fact independently of meteorological events and aftershocks.

These new findings are presented by a German-Franco-Japanese team of geoscientists in the current issue of the journal Geology, under the lead of the GFZ...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Networking conference in Heidelberg for outstanding mathematicians and computer scientists

20.08.2015 | Event News

Scientists meet in Münster for the world’s largest Chitin und Chitosan Conference

20.08.2015 | Event News

Large agribusiness management strategies

19.08.2015 | Event News

 
Latest News

Siemens sells 18 industrial gas turbines to Thailand

01.09.2015 | Press release

An engineered surface unsticks sticky water droplets

01.09.2015 | Materials Sciences

New material science research may advance tech tools

01.09.2015 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>