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Biologists need to monitor genes in order to understand how they create molecular changes in a cell leading to mistakes such as disease and malfunctions in the formation of organ systems. Now Brown University biologists have created a glowing green indicator for tracking ADAR, a crucial enzyme for editing RNA in the nervous system.
This advance gives scientists a way to view when and where ADAR is active in a living animal and how much of it is operating at any given time. In experiments in fruit flies, the researchers found surprising degrees of individual variation in ADAR's RNA editing activity in the learning and memory centers of the brains of individual flies.
Their work is described in the journal Nature Methods, which appears Dec. 25, 2011.
"We designed this molecular reporter to give us a fluorescent readout from living organisms," said Robert Reenan, professor of biology and senior author of the paper. "When it comes to gene expression and regulation, the devil is in the details."
Biologists already know that errors in transcribing RNA from DNA can lead to improper gene expression - how the gene functions - in the nervous system and might contribute to diseases such as epilepsy, suicidal depression, and schizophrenia.
More recently they've gathered evidence that ADAR is associated with disease. For instance in a study in Nature Neuroscience two months ago, Reenan and colleagues at the University of Pennsylvania described profound connections between ADAR and a model of Fragile X mental retardation in fruit flies.
Reenan feels that using this new "reporter" tool to look for correlations between ADAR activity levels and disease, might yield new insights into how RNA editing errors lead to individual variation.
He speculates that the fluorescent ADAR tracking system his research group has created could someday be adapted to fix a broken individual letter of RNA on an engineered gene.
"We're actually repairing RNA at the level of a single informational bit, or nucleotide," Reenan said. "Here we've shown we can take a mutant version of a gene and restore its function, but at the level of RNA rather than DNA."
A reporter of an editor
Reenan and Kyle Jay began working to create the reporter in 2006 working with a well-known tool of molecular biology: a jellyfish gene producing a protein that glows green when exposed to ultraviolet light.
Their intention was to break the gene in a way that ADAR is uniquely suited to fix.
They engineered the gene to glow green without mutating the DNA. Armed with their new ADAR reporter, Reenan and lead author James Jepson observed that ADAR activity is more pronounced in certain parts of the brains of developing larvae than it is in the brains of adults.
They also found wide variation in ADAR activity in the brains of flies of similar ages from individual to individual. This was a surprise, Reenan said, because all the flies are essentially genetically identical.
A versatile new tool?
Reenan is confident that the ADAR reporter can be useful in more organisms than the fruit fly.
The idea of creating the reporter grew out of his lab's studies in a number of species. ADAR is found in both invertebrates and vertebrates. In their paper the researchers describe testing the flexibility of their engineered jellyfish gene destined as it was for a fruit fly by splicing it to the intron of a moth.
"Thus a jellyfish-moth gene chimera was crippled by mutation, and repaired by a fruit fly enzyme," Reenan said.
"Rube Goldberg would be proud."
Reenan said he plans to use the ADAR reporter in flies to continue investigating genes associated with Fragile X. He's eager for someone who works on the disorder in mice to give it a try.
The idea of adapting this method to fix mistranscribed RNA or reverse DNA damage at the RNA level in a therapeutic fashion is for the future. But at least ADAR is now on the radar.
In addition to Reenan, Jepson, and Jay, the paper's other author is Yannis A. Savva. Jepson is also affiliated with Thomas Jefferson University in Philadelphia and Jay now works at the University of CaliforniaSan Francisco.
An Ellison Medical Foundation Senior Scholar award funded the research.
Original article: http://news.brown.edu/pressreleases/2011/12/adar