MicroRNAs, already implicated in cancer and normal development, latch on to and gum up larger strands of RNA that carry instructions for making the proteins that do all the cell’s work. They are, says Joshua Mendell, M.D., Ph.D., an assistant professor in the McKusick-Nathans Institute of Genetic Medicine at Hopkins, like “molecular rheostats that fine-tune how much protein is being made from each gene.”
That’s why normally microRNAs always have appeared to stick close to the cell’s protein-making machinery.
But during a survey of more than 200 of the 500 known microRNAs found in human cells, Mendell’s team discovered one lone microRNA “miles away” --- in cellular terms --- from all the others.
A weird unexpected result led to the discovery of how short sequences of RNA act like a sort of zip code for routing longer pieces of RNA.
Mendell's team discovered that 6 RNA nucleotide letters on the end of a microRNA control where in a cell the microRNAs get routed. By changing whihc 6 letters were on the end of a microRNA they could make the microRNA go to the nuclear rather than to the areas where most microRNAs are found.
Consisting of only 20 to 25 nucleotide building blocks (compared to other types of RNA that can be thousands of nucleotides long), each microRNA has a different combination of blocks. Mendell’s team realized that six building blocks at the end of the wayward miR-29b microRNA were noticeably different from the ends of other microRNAs.
Suspicious that the six-block end might have something to do with miR-29b’s location, the researchers chopped them off and stuck them on the end of another microRNA. When put into cells, the new microRNA behaved just like miR-29b, wandering far away from the cell’s protein-making machinery and into the nucleus, where the cell’s genetic material is kept.
Their ability to apply the same finding to a different kind of RNA opens up the possibility of using cellular RNA routing method to suppress genes for medical purposes.
The researchers then stuck the same six-block end onto another type of small RNA, a small-interfering RNA or siRNA that turns off genes. This also forced the siRNA into the nucleus.
According to Mendell, these results demonstrate for the first time that despite their tiny size, microRNAs contain elements consisting of short stretches of nucleotide building blocks that can control their behavior in a cell. Mendell hopes to take advantage of the built-in “cellular zip code” discovered in miR-29b as an experimental tool. For example, he plans to force other microRNAs and siRNAs into the nucleus to turn off specific sets of genes.
Since some genes suppress other genes. The ability to suppress some genes could also be used to turn up the activity of other genes.
Think of this discovery as equivalent to a computer programming hack. The ability to, for example, send small-interfering RNA (siRNA) into the nucleus means the ability to turn off specific genes. There's still the additional problem of how to get siRNA into cells in the first place. We need better gene therapy delivery mechanisms to do that. But once we get those mechanisms we'll be able to turn off specific genes in the nucleus. That could be used to suppress cancer or flip the state of genes for all sorts of other medical reasons.
|Share |||Randall Parker, 2007 January 08 11:16 PM Biotech Gene Hacking|