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New Study Expands Number of microRNAs in Human Genome

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NEW YORK (GenomeWeb) – While information in public databases point to approximately 1,900 locations in the human genome where microRNA are produced, new research out of Thomas Jefferson University indicates that this number is significantly greater.

The findings further reveal that many of these new loci are human- and tissue-specific, which has implications for research into the role of miRNAs in disease.

Since the first miRNA was discovered two decades ago, a growing number of the small, non-coding RNAs has been discovered and found to regulate a diversity of targets, while efforts to pin down the exact number of miRNAs within a given organism's genome continue.

Traditionally, it has been believed that miRNAs and their precursors are evolutionarily conserved, Isidore Rigoutsos, director of TJU's Computational Medicine Center and senior author of the new study, told GenomeWeb.

"Our position all along has been that [this restriction] prevents you from seeing things that could be useful," he said. "What we have been doing is try to liberate ourselves from this conservation constraint."

Several years ago, Rigoutsos and his team developed rna22, a method for identifying miRNA binding sites and their heteroduplexes, and used the tool to demonstrate the miRNAs can have a variety of targets beyond those based on seed region binding. And just last year, the team published evidence of even greater diversity in the miRNA targetome than previously anticipated.

In its latest work, Rigoutsos' group turned from miRNA targets to the small RNAs themselves, taking advantage newly available next-generation sequencing technologies while not limiting themselves by cross-genome conservation.

As detailed in the Proceedings of the National Academy of Sciences, the scientists examined roughly 1,300 short RNA sequencing datasets from 13 distinct human tissue types. From these they identified 3,707 statistically significant novel mature miRNAs arising from 3,494 novel precursors. About 91 percent of these were identified independently in 10 more of the samples analyzed.

Of this total, 45 percent were identified in 43 datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing, and represented three of the 13 tissues, indicating that these miRNAs are active in the RNA interference pathway.

"These results suggest that about half of our newly identified miRNAs are loaded onto the Ago-silencing complex and thus are imputed to be posttranscriptionally functional," the researchers wrote in the PNAS report.

In the context of sequence conservation across vertebrates and invertebrates, about 57 percent of the newly discovered miRNAs were found to be human-specific, with nearly 95 percent primate-specific.

Simply put, "there are a lot more microRNAs one can find if you remove the constraint of genome conservation," Rigoutsos said.

The scientists also discovered that many of the miRNAs they uncovered were tissue-specific, a key finding when it comes to developing drugs targeting the small RNAs.

As Rigoutsos noted, disrupting the activity of a disease-causing miRNA outside an affected tissue or organ can have deleterious results. Rather than developing ways to deliver a miRNA drug only to specific tissues, it may be simpler to focus on miRNAs that are confined to the diseased area.

Additionally, the fact that many miRNAs are human-specific means that many molecular interactions influenced by the small RNAs cannot be recapitulated in animal models — an important consideration for researchers and miRNA drug developers alike.

Even more miRNA

While the PNAS study uncovered roughly 3,400 new miRNAs, Rigoutsos stressed that the actual number is likely to be much higher in light of data he and his team reported last year.

In that work, the researchers presented data suggesting that isomiRs — species of mature miRNAs that arise from the same arm of a hairpin miRNA precursor and have different gene targets — that can vary depending on an individual's gender and ethnicity.

While conducting the experiments published in PNAS, he said, his team identified a number of isomiRs, but only presented the ones that were most abundant in the different tissues. As such, each arm of the newly identified miRNA-producing loci could potentially yield more than one product.

"Imagine, now, this added complexity in the context of the 3,400 new arms that we're presenting," he said.

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