Few genes underlie most microRNAs

Most microRNAs are not tissue-specific and many are expressed at trace levels, says new mammalian atlas

By | June 28, 2007

The vast majority of mammalian microRNAs originate from a surprisingly small number of microRNA genes, according to an atlas of microRNA expression published this week in Cell. The study also found that very few microRNAs are specific to individual tissues or cell types. Overall, the atlas quantifies microRNA expression in 26 types of normal and malignant tissues and cell types of humans and rodents. "They certainly have produced an extremely useful resource," said Victor Ambros of Dartmouth Medical School in Hanover, N.H., who was not involved in the work. They included "unprecedented diversity of tissue types in their survey and systematically characterized the microRNAs that are present there," he told The Scientist. MicroRNAs are small noncoding RNAs found in animals, plants, and viruses that regulate gene expression by interfering with messenger RNA function. Scientists have identified many microRNAs in mammals, but the expression levels and specificities of most of these microRNAs are not well-understood. The researchers, led by Pablo Landgraf of Rockefeller University in New York City, cloned and sequenced more than 300,000 sequences from 256 mammalian small RNA libraries. They found evidence for expression of about 400 microRNA genes in each genome -- a number considerably lower than some previous estimates, said Joshua Mendell of John Hopkins University in Baltimore, Md., who did not participate in the study. "The significance of these remaining hundreds of microRNA genes that have been cloned" in other studies is unclear, Mendell said. The authors also found that 97% of the microRNA clones they sequenced originated from fewer than 300 of the microRNA genes. "This suggests that many microRNAs are generally produced at a low background level across tissues," co-author Mihaela Zavolan of the University of Basel in Switzerland told The Scientist in an Email. "We cannot make definite inferences about the functional role of these 'trace' microRNAs at this time," but it's possible that many of them may not be functionally relevant, she said. She and her colleagues also found that these rare microRNAs were usually poorly conserved between species. The authors discovered very few microRNAs specific to individual tissues or cell types. Instead, "differences between cell lineages and tissue types are frequently limited to expression changes in only a small set of microRNAs," Zavolan said, "many of which are ubiquitously expressed, but at different levels in different lineages and tissues." This lack of specificity "doesn't mean [microRNAs are] not useful for classifying tissues or cell types or origins of tumors," Mendell said. "What is really important is the sum and combination of microRNAs that are expressed in a given sample." The study identified only 33 new mammalian microRNAs. "This is really a very extensive study," Ambros said, "and the fact that they identified only a few dozen additional microRNAs indicates that we may be converging on a reasonably complete catalog of microRNAs in mammals, at least of the more abundant microRNAs in the major organs and tissues." It's still possible that some functionally important microRNAs are expressed only in rare cell types, and so don't show up in this screen, Ambros added. The microRNA expression atlas the researchers compiled contains many other useful pieces of information about microRNA structures, sequences, expression patterns, and evolution, Ambros told The Scientist. "It's a marvelously thorough study," he said. "This is a baseline database that's going to be really important for people studying the world of microRNAs in development and disease." Melissa Lee Phillips mail@the-scientist.com Links within this article D. Steinberg, "MicroRNA target practice," The Scientist, June 20, 2005. http://www.the-scientist.com/article/display/15538/ P. Landgraf et al., "A Mammalian microRNA expression atlas based on small RNA library sequencing," Cell, June 29, 2007. http://www.cell.com C.Q. Choi, "MicroRNA mutations abundant," The Scientist, June 5, 2006. http://www.the-scientist.com/news/display/23533/ Victor Ambros http://chronic.dartmouth.edu/VRA/ambroslab.html E. Weinholds and R.H. Plasterk, "MicroRNA function in animal development," FEBS Letters, October 31, 2005. http://www.the-scientist.com/pubmed/16111679 Pablo Landgraf http://www.rockefeller.edu/labheads/tuschl/members.html E. Berezikov et al., "Phylogenetic shadowing and computational identification of human microRNA genes," Cell, January 14, 2005. http://www.the-scientist.com/pubmed/15652478 Joshua Mendell http://www.hopkinsmedicine.org/geneticmedicine/People/Faculty/mendell.html Mihaela Zavolan http://www.biozentrum.unibas.ch/zavolan/index.html J.M. Perkel, "MicroRNA evolution put to the test," The Scientist, October 30, 2006. http://www.the-scientist.com/news/display/25713/

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