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IBM, GIS Stem Cell Study Shows MicroRNAs Target Multiple Coding Regions

NEW YORK (GenomeWeb News) – Research on the role of microRNAs in stem cell differentiation is providing new insights into RNA interference in general.
 
Conventional wisdom holds that miRNAs mainly target conserved sequences in the 3’ untranslated region, or UTR, of messenger RNA. But the latest research, appearing online today in Nature, suggests that miRNA can also target multiple sites in amino acid coding sequences. Researchers from IBM and the Genome Institute of Singapore made the discovery while using mathematical modeling and mouse studies to investigate the roles of three miRNAs and three transcription factors in mouse stem cell differentiation.
 
“We have made yet another step towards understanding the intricate nature of microRNAs and the roles they play in the regulation of cellular processes,” co-senior author Isidore Rigoutsos, manager of the bioinformatics group at IBM Research’s Computational Biology Center, said in a statement. “The finding that microRNAs can extensively target locations in the amino acid coding regions of a transcript is an exciting discovery and reveals another important aspect of microRNA activity.”
 
In general, miRNAs down-regulate mRNA post-transcriptionally by targeting mRNA for degradation or otherwise interfering with translation. Because miRNAs were first shown to act on the 3’ UTR of mRNAs, much miRNA research has focused on interactions with this mRNA region.
 
“For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3’ untranslated regions of mRNAs, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity,” the authors wrote.
 
But a mathematical model developed by IBM scientists in 2006 “predicted an abundance of miRNA targets beyond the confines of a 3’ UTR.” For this study, Rigoutsos and colleagues tested their hypotheses in mouse embryonic stem cells, focusing on the genes for three key stem cell transcription factors — Nanog, Oct4, and Sox2.
 
When they used retinoic-acid to prompt mouse embryonic stem cell differentiation, the researchers found that three miRNAs — miR-134, miR-296, and miR-470 — were up-regulated in a differentiation-dependant manner. As predicted by their computational analysis, subsequent experiments indicated that these miRNAs each target multiple coding regions of the Nanog, Oct4, and Sox2 genes.
 
When the researchers introduced silent mutations into the coding regions of the transcription factors, the miRNAs could not bind the mRNA, interfering with differentiation.
 
On the other hand, transfecting mouse embryonic stem cells with pre-miRNAs for either miR-296 or mir-470 nudged the stem cells into a more differentiated state.
 
“[A] single microRNA forced into the powerful embryonic stem cell can impose differentiation,” co-senior author Bing Lim, senior group leader at the Genome Institute of Singapore, said in a statement. “This is exciting because one could envisage using microRNAs as a small molecule to control the differentiation of stem cells, or to make new stem cells.”
 
Interestingly enough, the coding sequences targeted by the three miRNAs were not necessarily conserved between mice and rhesus monkeys. That means miRNA targets may be more difficult to catalogue than previously believed, since simply aligning targeted sequences would miss some miRNA targets.
 
“This work is a great example of how future medical discovery will progressively require the joint efforts of computer scientists working in conjunction with biologists,” Edison Liu, executive director of the Genome Institute of Singapore, said in a statement. “But in the end, it still boils down to doing the lab experiment.”

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