Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

'Activating' RNA takes DNA on a loop through time and space

18.02.2013
Links for disease and role in embryonic development

Long segments of RNA— encoded in our DNA but not translated into protein—are key to physically manipulating DNA in order to activate certain genes, say researchers at The Wistar Institute. These non-coding RNA-activators (ncRNA-a) have a crucial role in turning genes on and off during early embryonic development, researchers say, and have also been connected with diseases, including some cancers, in adults.

In an online article of the journal Nature, a team of scientists led by Wistar's Ramin Shiekhattar, Ph.D., detail the mechanism by which long non-coding RNA-activators promote gene expression. They show how these RNA molecules help proteins in the cell to create a loop of DNA in order to open up genes for transcription. Their experiments have also described how particular ncRNA-a molecules are related to FG syndrome, a genetic disease linked to severe neurological and physical deficits. "These ncRNA-activators can activate specific genes by working with large protein complexes, filling in a big piece of the puzzle," said Shiekhattar, Herbert Kean, M.D., Family Professor and senior author of the study. "Our DNA encodes thousands of these ncRNA-activators, each with a role in timing the expression of a specific gene. As we learn more about non-coding RNA, I believe we will have a profoundly better understanding of how our genes function."

Their findings also provide a plausible mechanism of how locations along chromosomes, classically known as "enhancer" elements, can influence the expression ("reading") of genes located 5,000 to 100,000 base pairs ("letters") of DNA away. According to their findings, ncRNA-a molecules bind to large protein complexes to form a loop of DNA, which then opens up the gene to the molecular machinery that transcribes DNA. "There is an abundance of evidence to indicate that enhancers are critical components of transcription during embryonic development and disease process," Shiekhattar said.

"Non-coding RNAs are probably one of the earliest molecules that determine spatial and temporal gene expression in a developing embryo," Shiekhattar said. "These enhancers can help turn genes on and off as a growing embryo would need, but as we have seen in other genetic mechanisms of embryonic development, they can lead to cancer if they are switched on inappropriately in adult cells."

In the classic "central dogma" of biology, chromosomal DNA is transcribed into RNA, which is then translated by the cell into proteins. In recent years, however, scientists have found that not all transcribed RNA molecules become translated into proteins. In fact, studies have shown that large portions of the genome are transcribed into RNA that serve tasks other than functioning as blueprints for proteins. In 2010, the Shiekhattar lab first published the discovery of these ncRNA enhancer molecules in the journal Cell (2010 Oct 1;143(1):46-58), and theorized on their role as "enhancers" of gene expression. Since then, laboratories around the world have published and linked ncRNAs not only to transcriptional enhancers but also to certain diseases, including some cancers.

To discover how such enhancer-like RNAs function, the Shiekhatter laboratory deleted candidate molecules with known roles in activating gene expression, and assessed if they were related to RNA-dependent activation. They found that depleting components of the protein complex known as Mediator specifically and potently diminished the ability of ncRNA-a to start the process of transcribing a gene into RNA. Further, they found that these activating ncRNAs can attach to Mediator at multiple locations within the Mediator protein complex, and Mediator itself can interact with the enhancer element site on DNA that encodes these activating ncRNAs. Their results also determined how mutations in a protein that makes up the Mediator complex, called MED12, drastically diminishes Mediator's ability to associate with activating ncRNAs.

Mutations in the MED12 protein are a marker for FG syndrome (also know as Opitz–Kaveggia syndrome), a rare genetic disorder that leads to abnormalities throughout the body and varying degrees of physical and neurological problems. "This clearly shows how activating ncRNAs can influence disease development, an idea that has been gaining evidence in the scientific literature," Shiekhattar said. To confirm that ncRNA-a works with Mediator to form a loop in DNA, the researchers used a technique called chromosome conformation capture (3C) to gain a better understanding of the three-dimensional structure of chromosomes. Their results show how Mediator gets a foothold of sorts on the portion of DNA that encodes the ncRNA-a, and twists the DNA to form a loop.

"The looping mechanism serves to physically bring together a distant enhancer element with the start site of the targeted gene, allowing Mediator to recruit the proteins responsible for reading the gene to the location," Shiekhattar said. "It is at least one answer to how these classical enhancer elements function while being physically distant from their target genes."

The Shiekhattar laboratory is supported by grants from the National Institutes of Health (P30 CA 010815).

Wistar co-authors include Fan Lai, Ph.D., lead author, and Matteo Cesaroni, Ph.D., postdoctoral fellows in the Shiekhattar laboratory. Co-authors include Ulf Andersson Ørom, Ph.D., Max Planck Institute for Molecular Genetics; Malte Beringer, Ph.D., Center de Regulacio Genomica, Barcelona; Dylan J. Taatjes, Ph.D., University of Colorado; and Gerd A. Blobel, M.D., Ph.D., The Children's Hospital of Philadelphia.

Greg Lester | EurekAlert!
Further information:
http://www.wistar.org

More articles from Life Sciences:

nachricht Quasi-sexual gene transfer drives genetic diversity of hot spring bacteria
29.05.2015 | Carnegie Institution

nachricht Scientists use unmanned aerial vehicle to study gray whales from above
29.05.2015 | NOAA National Marine Fisheries Service

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Lasers are the key to mastering challenges in lightweight construction

Many joining and cutting processes are possible only with lasers. New technologies make it possible to manufacture metal components with hollow structures that are significantly lighter and yet just as stable as solid components. In addition, lasers can be used to combine various lightweight construction materials and steels with each other. The Fraunhofer Institute for Laser Technology ILT in Aachen is presenting a range of such solutions at the LASER World of Photonics trade fair from June 22 to 25, 2015 in Munich, Germany, (Hall A3, Stand 121).

Lightweight construction materials are popular: aluminum is used in the bodywork of cars, for example, and aircraft fuselages already consist in large part of...

Im Focus: Solid-state photonics goes extreme ultraviolet

Using ultrashort laser pulses, scientists in Max Planck Institute of Quantum Optics have demonstrated the emission of extreme ultraviolet radiation from thin dielectric films and have investigated the underlying mechanisms.

In 1961, only shortly after the invention of the first laser, scientists exposed silicon dioxide crystals (also known as quartz) to an intense ruby laser to...

Im Focus: Advance in regenerative medicine

The only professorship in Germany to date, one master's programme, one laboratory with worldwide unique equipment and the corresponding research results: The University of Würzburg is leading in the field of biofabrication.

Paul Dalton is presently the only professor of biofabrication in Germany. About a year ago, the Australian researcher relocated to the Würzburg department for...

Im Focus: Basel Physicists Develop Efficient Method of Signal Transmission from Nanocomponents

Physicists have developed an innovative method that could enable the efficient use of nanocomponents in electronic circuits. To achieve this, they have developed a layout in which a nanocomponent is connected to two electrical conductors, which uncouple the electrical signal in a highly efficient manner. The scientists at the Department of Physics and the Swiss Nanoscience Institute at the University of Basel have published their results in the scientific journal “Nature Communications” together with their colleagues from ETH Zurich.

Electronic components are becoming smaller and smaller. Components measuring just a few nanometers – the size of around ten atoms – are already being produced...

Im Focus: IoT-based Advanced Automobile Parking Navigation System

Development and implementation of an advanced automobile parking navigation platform for parking services

To fulfill the requirements of the industry, PolyU researchers developed the Advanced Automobile Parking Navigation Platform, which includes smart devices,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International symposium: trends in spatial analysis and modelling for a more sustainable land use

20.05.2015 | Event News

15th conference of the International Association of Colloid and Interface Scientists

18.05.2015 | Event News

EHFG 2015: Securing health in Europe. Balancing priorities, sharing responsibilities

12.05.2015 | Event News

 
Latest News

Quasi-sexual gene transfer drives genetic diversity of hot spring bacteria

29.05.2015 | Life Sciences

First Eastern Pacific tropical depression runs ahead of dawn

29.05.2015 | Earth Sciences

Donuts, math, and superdense teleportation of quantum information

29.05.2015 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>