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Junk DNA: "Listen to your junk man - he's singing"

"Listen to your junk man - he's singing ... All dressed up in satin, walking past the alley..." - Bruce Springsteen, New York Serenade

Junk DNA is looking mighty fine lately. Only a few years ago, the non-coding regions of DNA that make up over 95% of the genome were looked upon as the uninteresting desert wastelands between the regions of DNA involved in protein synthesis. How times have changed!

'Junk' DNA not junk but key to complexity

There's a very nice video on Gene Regulation(free) from Science Magazine that discusses the pivotal roles that these non-coding regions of DNA play in our genome.

As John Mattick of The University of Queensland states at the end of the video:"We're just realizing that we've only got to first base and we have a long way to go, and most of the journey forward is going to be dissecting, analyzing and rebuilding an understanding of the massively parallel and extremely sophisticated RNA regulatory circuits, which really do underpin our complexity. And the irony, I think, is that what was dismissed as junk, because it wasn't understood, will turn out to hold the secret of human complexity, including our cognitive complexity. And that's where were going over the next 10 to 15 years.

More info on John Mattick's work is provided by a News in Science article (May 10,2004):The researchers scanned the human, rat and mouse genomes for matching regions of 200 or more DNA base pairs and found 481 regions that were completely unchanged. They then looked at earlier organisms.

"We then looked at the dog and bovine genomes and found that they were preserved there. Amazingly, most of them were preserved in the chicken genome, which has just been released, and about half are preserved in fish," Mattick said. "So that means some of these sequences have remain unchanged during evolution for over 400 million years."

Mattick said that these sequences remained unchanged while protein-coding genes changed slowly through evolution.

"So whatever [these conserved regions] are, and whatever they're doing, evolution is really saying that they're critical to our biology in ways that we don't yet understand."

Mattick said some of the sequences overlapped with protein-coding genes, while some were outside genes. But all were strongly associated with genes involved in controlling development. "They're almost certainly regulatory," he said.

The blog post on RNA interference provides some further details on the role RNA plays in transcriptional gene regulation. Additional info on RNA splicing in dendrites is provided in the blog post on dendritic spines. But there's a lot more going on here...

For one thing, function specific proteins can be 'stockpiled' in 'cytoplasmic granules', as well as sent to these granules for destruction. From The Scientist - A New View of Translational Control (Dec. 5, 2005): "Researchers are rapidly uncovering so-called granules in the cytoplasm that cluster function-specific proteins for RNA storage, silencing, reuse, destruction, and perhaps even splicing. Apparently related to the well characterized maternal mRNA granules that jumpstart embryogenesis, these neighborhood processing centers serve important functions in adult cells, including shaping synaptic plasticity and responding to stress.
"I think we'll learn that how cells control the destruction and translation of messenger RNAs through these structures will be a fundamental part of the control of genetic expression," says Roy Parker at the University of Arizona in Tucson. In the past two years, Parker has found cytoplasmic structures containing mRNA decapping and degradation enzymes. These compartments first appeared to serve as an mRNA junkyard: Transcripts with shortened poly(A) tails, or those otherwise no longer needed were relegated here for destruction. Parker dubbed them processing bodies, or P-bodies.
"It makes sense to have compartments for degradation. It's not just RNA randomly floating around with an enzyme happening to find it," says Keith Blackwell at Joslin Diabetes Center in Boston. But P-bodies may be more than just centralized paper shredders; they may store mRNA for later use. In September, when Parker and colleagues blocked translation in yeast cells by depriving them of glucose, the number of free-floating ribosome complexes known as polysomes decreased, and P-bodies grew in size as mRNAs went to them.5 But instead of being degraded, mRNAs accumulated. When glucose was restored, P-body size decreased and polysome number rose, suggesting that mRNAs were getting reused for translation. Reusing old mRNAs is likely more efficient and faster than making new ones, says John Rossi at the Beckman Research Institute of the City of Hope in Duarte, Calif.
In neurons, mRNA granules seem to influence synaptic plasticity (the variability in a synapse's signal strength), which appears fundamental to memory formation and learning. Kosik and colleagues found that granules store translationally silent mRNAs in dendrites. When the cell is depolarized, Kosik hypothesizes that the granules release their mRNAs to polysomes, resulting in localized protein changes. "They make sure that translation is directed to specific locations and not in the wrong place," he explains. The importance of such systems is hard to predict, Kosik says: "We could be talking about a branch of biology as extensive and intricate as the study of how proteins are directed to their destinations." Parker notes that neuronal and maternal granules have proteins in common and says he's looking to see if neuronal granules also possess P-body proteins.

More recently, James H. Eberwine of U.Penn reports in his web page: We have shown that multiple mRNAs are localized in neuronal dendrites and have provided a formal proof of local mRNA translation in dendrites. Further, we have recently shown that the intracellular sites of localization and translation of these mRNAs can be altered by synaptic stimulation highlighting for the first time that in vivo translation of a mRNA can occur at different rates in distinct regions of a single cell (translation is primarily exponential in dendrites and linear in the cell soma).

More info on the work of Eberwine and colleagues is described in an article in The Medical News: RNA-associated introns guide nerve-cell channel production:In nerve cells, some ion channels are located in the dendrite, which branch from the cell body of the neuron. Dendrites detect the electrical and chemical signals transmitted to the neuron by the axons of other neurons. Abnormalities in the dendrite electrical channel are involved in epilepsy, neurodegenerative diseases, and cognitive disorders, among others.

Introns are commonly looked on as sequences of "junk" DNA found in the middle of gene sequences, which after being made in RNA are simply excised in the nucleus before the messenger RNA is transported to the cytoplasm and translated into a protein. In 2005, the Penn group first found that dendrites have the capacity to splice messenger RNA, a process once believed to only take place in the nucleus of cells.

Now, in the current study, the group has found that an RNA encoding for a nerve-cell electrical channel, called the BK channel, contains an intron that is present outside the nucleus. This intron plays an important role in ensuring that functional BK channels are made in the appropriate place in the cell.

When this intron-containing RNA was knocked out, leaving the maturely spliced RNA in the cell, the electrical properties of the cell became abnormal. “We think the intron-containing mRNA is targeted to the dendrite where it is spliced into the channel protein and inserted locally into the region of the dendrite called the dendritic spine. The dendritic spine is where a majority of axons from other cells touch a particular neuron to facilitate neuronal communication” says Eberwine. “This is the first evidence that an intron-containing RNA outside of the nucleus serves a critical cellular function.”

“The intron acts like a guide or gatekeeper,” says Eberwine. “It keys the messenger RNA to the dendrite for local control of gene expression and final removal of the intron before the channel protein is made. Just because the intron is not in the final channel protein doesn't mean that it doesn't have an important purpose.”

The group surmises that the intron may control how many mRNAs are brought to the dendrite and translated into functional channel proteins. The correct number of channels is just as important for electrical impulses as having a properly formed channel.

The investigators believe that this is a general mechanism for the regulation of cytoplasmic RNAs in neurons. Given the central role of dendrites in various physiological functions they hope to relate this new knowledge to understanding the molecular underpinnings of memory and learning, as well as components of cognitive dysfunction resulting from neurological disease.

So it really seems that each dendrite is remarkably self-contained, with its own mitochondrial energy supply, the ability to synthesize proteins and the ability to wharehouse proteins. And that the dendritic machinery can be dynamically reconfigured by the neuron based on synaptic activity - the mitochondria and the mRNA localization and translation sites can move from quiescent dendrites to active ones on demand.

Junk DNA has other secrets that are being discovered, as well - for example, RNA-guided mechanisms underlying genome rearrangement. From a recent article in ScienceDaily (May 21, 2009): Laura Landweber and other members of her team are researching the origin and evolution of genes and genome rearrangement, with particular focus on Oxytricha because it undergoes massive genome reorganization during development.

In her lab, Landweber studies the evolutionary origin of novel genetic systems such as Oxytricha's. By combining molecular, evolutionary, theoretical and synthetic biology, Landweber and colleagues last year discovered an RNA (ribonucleic acid)-guided mechanism underlying its complex genome rearrangements.

"Last year, we found the instruction book for how to put this genome back together again -- the instruction set comes in the form of RNA that is passed briefly from parent to offspring and these maternal RNAs provide templates for the rearrangement process," Landweber said. "Now we've been studying the actual machinery involved in the process of cutting and splicing tremendous amounts of DNA. Transposons are very good at that."
They have concluded that the genes spur an almost acrobatic rearrangement of the entire genome that is necessary for the organism to grow.

It all happens very quickly. Genes called transposons in the single-celled pond-dwelling organism Oxytricha produce cell proteins known as transposases. During development, the transposons appear to first influence hundreds of thousands of DNA pieces to regroup. Then, when no longer needed, the organism cleverly erases the transposases from its genetic material, paring its genome to a slim 5 percent of its original load.

"The transposons actually perform a central role for the cell," said Laura Landweber, a professor of ecology and evolutionary biology at Princeton and an author of the study. "They stitch together the genes in working form." The work appeared in the May 15 edition of Science.

Listen to your junk man - he's singing!


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