Study finds nearly one-third of human genome regulated
by RNA
CAMBRIDGE, Mass. (Jan. 14, 2005) — For many years,
DNA and proteins have been viewed as the real movers
and shakers in genomic studies, with RNA seen as little
more than a messenger that shuttles information between
the two. But researchers from Whitehead Institute for
Biomedical Research and Massachusetts Institute of Technology
have discovered that small RNA molecules called microRNAs
regulate thousands of human genes—more than one
third of the genome’s protein-coding regions.
In other words, a class of molecule once relegated to
the sidelines may be one of the principal players in
regulating cellular mechanisms.
“It’s exciting to see how many genes are
regulated by microRNAs. We now know that this type of
gene control is much more widespread than previously
appreciated,” says Whitehead Member and MIT professor
of biology David
Bartel.
MicroRNAs interrupt a gene’s ability to make
protein. These tiny, single-stranded pieces of RNA are
newcomers to biological research. It wasn’t until
2000 that researchers even knew that microRNAs existed
in humans. Now, in the January 14 edition of the journal
Cell, Benjamin Lewis, a graduate student working
jointly with Whitehead’s Bartel and MIT associate
professor of biology Christopher Burge, provides the
first evidence that microRNAs influence a large percentage
of life’s functions.
The team developed a computational method to define
the relationship between microRNAs and their target
genes. In December 2003, the same group identified 400
genes in the human genome targeted by microRNAs. (Prior
to this study, there were no known microRNA targets
in any vertebrate.)
In their latest paper, taking advantage of the most
recent genome-sequencing data, the team has compared
human genome data with that of the dog, chicken, mouse,
and rat. For each of the microRNAs and protein-coding
genes that are common to these five species, the team
looked for correspondence between the microRNAs and
the protein-coding genes. They discovered that regulation
of a third of these genes has been preserved since the
last common ancestor of mammals and chicken, which lived
310 million years ago. “This study is an excellent
example of the power of comparative genomics to illuminate
how human genes are regulated,” says Burge.
“As more genome data becomes available and the
technology becomes more sophisticated, I think we’ll
find that even more genes are targeted by microRNAs,”
predicts Lewis.
In addition, the team discovered some hints about how
microRNAs find their targets.
To produce a protein, the cell first makes a template
for that protein by constructing a molecule called messenger
RNA. MicroRNAs inhibit protein production by associating
themselves with particular messenger RNAs, thereby reducing
the amount of protein that’s ultimately produced.
In this study, the researchers determined which portion
of the microRNA is most important for this process,
and identified additional determinants in the messenger
RNA that are likely to contribute to recognition by
microRNAs.
These findings contribute to the recent interest in
potential therapeutic uses of RNA. For example, using
a technique known as RNA interference, or RNAi, researchers
are shutting off genes by delivering into cells artificial
microRNA-like molecules called siRNAs. RNAi has already
transformed how many labs are investigating gene functions,
and siRNAs are being developed for clinical applications.
Learning more about how microRNAs operate in human cells
should help scientists to understand how best to exploit
siRNAs for treating disease.
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