Feb. 17, 2013 ? 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. 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 Philadelphia Inquirer discussed these findings with Shiekhattar, and he reveals why he refers to them views ncRNA-activators as the "dark matter of biology."
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The above story is reprinted from materials provided by The Wistar Institute.
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Journal Reference:
- Fan Lai, Ulf A. Orom, Matteo Cesaroni, Malte Beringer, Dylan J. Taatjes, Gerd A. Blobel, Ramin Shiekhattar. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature, 2013; DOI: 10.1038/nature11884
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Source: http://feeds.sciencedaily.com/~r/sciencedaily/most_popular/~3/lM5a2W4vYcE/130217134240.htm
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We all go through phases where we feel like we’ve seen every possible Kickstarter project that we’d ever want and then one like Mycestro comes along and reminds us that this is just the tip of the iceberg. It’s a 3D mouse that you strap to one of your fingers and it looks like it could become a huge asset for multi-tasking. If you think about how you use your computer, be it a desktop or laptop, you know that your hands move from the keyboard to the trackpad or mouse constantly, over and over again. It’s wasted movement for the most part, especially when you see the possibilities that Mycestro unlocks. The only thing left is for this thing to get funded, because it looks like all of the prototypes work perfectly. Its founder and creator, Nick Mastandrea, has been tinkering on this project for quite a while, having been featured in Engadget a few years ago, but it looks like it’s ready for primetime. You’ll be able to pick one up for a $79 pledge in white, or $99 with your choice of color. The estimated shipping date is sometime in October of this year, if all goes well. Have a look at some of its features, which include touch buttons that allow you to navigate your computer without the need of moving your entire and to a dedicated area on a computer, thanks to 3D technology and space recognition: Here are the specs for the 3D Mouse: - Size of a wireless earpiece. - Light, weighing next to nothing. - Internal battery can be charged via USB. - Battery life is estimated to be eight hours depending on usage. - Two different replaceable clip sizes. This isn’t a completely perfect situation though, as you’ll have to re-learn how to use a mouse. The other thing is that if you’re in a coffee shop or somewhere in public, people are going to look at you like you have some issues. The thing is called the Mycestro for a reason, it looks like you’re conducting your own private orchestra. In other words, you’re going to look weird. If you’re OK with that, then the benefits outweigh the public shame and looks you might receive. The device works from 30 feet away from your computer, thanks to bluetooth, so you could use this for presentations at work. The touch technology