Researchers at Johns Hopkins have discovered that a
tiny piece of genetic code apparently goes where no bit of
it has gone before, and it gets there under its own
internal code.
A report on the renegade ribonucleic acid, and the
code that directs its movement, was published Jan. 5 in
Science.
MicroRNAs, already implicated in cancer and normal
development, latch onto 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, an
assistant professor in the McKu
sick-Nathans Institute of Genetic Medicine at Johns
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.
Hun-Way Hwang, a graduate student in human genetics
and contributor to the study, said, "It was so clearly in
the wrong place at the wrong time for what we thought it
was supposed to be doing that we just had to figure out
why."
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 off
the six 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.
The researchers then stuck the same six-block end onto
another type of small RNA, a small-interfering RNA 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 small-interfering RNAs into the nucleus to
turn off specific sets of genes.
Mendell's team is actively hunting for additional
hidden microRNA elements that control other aspects of
their behavior in cells. The scientists also are curious to
figure out what miR-29b is doing in the nucleus. Because
microRNAs have been implicated in cancer as well as normal
development, Mendell hopes that further study of miR-29b
will reveal other hidden functions of microRNAs.
The research was funded by the March of Dimes, Rita
Allen Foundation and Lustgarten Foundation for Pancreatic
Cancer Research.
Authors on the paper are Hwang, Erik Wentzel and
Mendell, all of Johns Hopkins.
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