An entire class of seemingly useless genetic components may actually regulate gene activity, suggests a study that -- though preliminary -- has potentially transformative implications for biology.
The findings involve apparently redundant copies of genes, called "pseudogenes," and RNA molecules that would normally carry out genetic instructions, but appear to be disabled.
When it comes to altering the activity of PTEN, a cancer tumor-regulating gene, these components are neither redundant nor broken. Instead they help turn PTEN on and off.
The same might happen for thousands of other genes. If so, the findings have revealed an entire new class of operators in the programming language of life.
"This is a completely new way by which genes can be regulated. It's something that up to this point has been undiscovered," said Leonardo Salmena, a Harvard Medical School geneticist and co-author of the study, published June 23 in Nature.
The implicit question is whether the process is unique to PTEN and its decoys, or applies to the human genome's other 19,000 pseudogenes. If so, the junk may actually be vitally important to development and disease.
"There's a huge domain of non-coding RNAs. Until now, we couldn't make sense of them," said study co-author Pier Paolo Pandolfi, also a Harvard Medical School geneticist. "Now we have a way to understand them. We're not in the dark."
Scientists have been aware of RNA since the 1960s, when they learned that genes code for what's now known as messenger RNA, which carry instructions to protein-manufacturing cellular factories. But the straightforward messenger model proved simplistic.
Other types of RNA, called microRNA and small interfering RNA, can bind to messenger RNA. This prevents gene instructions from reaching their destinations, and allows for fine-tuned gene control. Gene activity can be quickly shut off, and just as quickly allowed to proceed.
So-called RNA interference is now considered essential for coordinating the ultra-fast, ultra-complicated mixing-and-matching of proteins that takes place in every single cell, all the time. In 2006, the discoverers of RNA interference received a Nobel Prize. Researchers anticipated an RNA revolution.
In the latest study, the researchers flipped the standard script of RNA interference. Inspired by MIT geneticist Phil Sharp's discovery that synthetic messenger RNA could be used to trap microRNA -- interfering with the interferer, so to speak -- they wondered if cells might not already do that.
Indeed, each human genome has many pseudogenes, or near-perfect copies of functional genes. These pseudogenes produce RNA that doesn't seem to do anything, but simply floats in cellular space. Scientists have long assumed pseudogenes and their RNA to be so much cruft, the biological equivalent of leftover code that's yet to be excised from a program. But the researchers in this study, whose specialty is a tumor-suppressing gene called PTEN, noticed that RNA produced by PTEN's pseudogenes was shaped exactly like the real thing.
They hypothesized that PTEN's pseudogene RNA should work like a decoy, pulling in microRNA and small interfering RNA, allowing PTEN's messenger RNA to proceed unobstructed. Experiments showed that their guess was right.
To test their proposition, the researchers first amplified the expression of PTEN pseudogenes in laboratory cell cultures. As predicted, this increased PTEN protein production: The decoys did their job. When the researchers decreased PTEN pseudogene expression, PTEN protein levels fell. In mice, decreased PTEN expression often leads to cancer.
The researchers then studied expression levels of PTEN and its pseudogenes in samples of cancerous tissue, and found the patterns duplicated. It wasn't only PTEN that helped suppress tumors, but supposed junk. In their absence, would-be interfering RNA was unleashed.
The researchers dubbed the decoys "competitive endogenous RNA," or ceRNA. They speculate that regular messenger RNA could also function as ceRNA, as could non-coding RNA that's not produced by pseudogenes but hasn't yet been functionally identified.
According to Pandolfi, if the findings truly represent a widespread new class of RNA, they will double the known number of functional genetic elements.
"This brings into play thousands of RNAs that we previously had no idea what they did," said Salmena. "We think we've only hit the tip of the iceberg with this phenomena."
In two accompanying Nature commentaries, Thomas Jefferson University geneticist Isidore Rigoutsos and University of California, San Diego geneticist Frank Furnari lauded the work's immediate implications for cancer.
Furnari noted that altered PTEN gene expression patterns are seen in Cowden's disease and Bannayan-Zonana syndrome, raising the possibility that ceRNA is involved in those rare diseases. Rigoutsos agreed that the findings "could have broader implications beyond PTEN regulation."
"They made a very exciting observation. It raises the question of whether there's another level of regulation of gene expression," said Dinah Singer, a geneticist at the National Cancer Institute, which helped fund the research. "Having made this observation, you can now look anywhere for it."
Singer declined to speculate on whether the newly described mechanism might eventually account for the so-called missing heritability, a term used by scientists to describe genetic risk factors that clearly exist but can't be linked to standard gene mutations.
"To what extent this is going to be a general mechanism, the onus is now on the scientific community to begin looking in other systems," said Singer. "I presume they will."
Image: Intensity of PTEN gene expression in normal and cancerous prostate tissue./Nature.
See Also:
- Beyond the Genome
- Rare Gene Glitch a Clue to Genomics Mystery
- The Human Genome in 3 Dimensions
- Complex Life Traced to Ancient Gene Parasites
- Twin Study Deepens Multiple Sclerosis Mystery
- 10 Years on, 'The Genome Revolution Is Only Just Beginning
Citations: "A coding-independent function of gene and pseudogene mRNAs regulates tumour biology." By Laura Poliseno, Leonardo Salmena, Jiangwen Zhang, Brett Carver, William J. Haveman & Pier Paolo Pandolfi. Nature, Vol. 465 No. 7301, June 23, 2010.
"Decoy for microRNAs." By Frank Furnari and Isidore Rigoutsos. Nature, Vol. 465 No. 7301, June 23, 2010.
Brandon Keim's Twitter stream and reportorial outtakes; Wired Science on Twitter. Brandon is currently working on a book about ecological tipping points.
