Computational Biology Group Identifies New Mechanism Of Gene Regulation

MIT scientists have found a new way that DNA can carry out its work that is
about as surprising as discovering that a mold used to cast a metal tool can
also serve as a tool itself, with two complementary shapes each showing
distinct functional roles.



Professor Manolis Kellis and postdoctoral research fellow Alexander Stark
report in the January 1 issue of the journal Genes & Development that in
certain DNA sequences, both strands of a DNA segment can perform useful
functions, each encoding a distinct molecule that helps control cell
functions.



DNA works by complementarity: paired DNA strands serve as a template for
each other during DNA replication, and ordinarily only a single DNA strand
serves as a template to produce RNA strands, which then go on to produce
proteins. The process is similar to the way each bump or dent in a mold is
paired with a corresponding dent or bump in the resulting molded object.



While many RNAs are eventually translated into proteins with specific
functions, some RNA molecules instead act directly, carrying out roles
inside the cell. Certain RNA genes, known as microRNAs, have been shown to
play important regulatory roles in the cell, often coordinating important
events during the development of the embryo. These microRNAs fold into
relatively simple hairpin structures, with two stretches of near-perfect
complementary sequence folding back onto each other. One of the two
'arms' of a hairpin is then processed into a mature microRNA.



The surprising discovery is that for some microRNA genes, both DNA
strands, instead of just one, encode RNA, and both resulting microRNAs
fold into hairpins that are processed into mature microRNAs. In other
words, both the tool and its mold appear to be functional. Kellis and
Stark found two such microRNA pairs in the fruit fly, and eight more such
pairs in the mouse.



The idea that there could be such dual-function strands, where both DNA
strands encode functional RNA products, "had never even been
hypothesized," Kellis says. But followup work confirmed that they did
indeed function in this way. The work suggests that other such unexpected
pairings, with both DNA strands encoding important functions, may also
exist in a variety of species.



This discovery builds on a similar, earlier surprising finding about
microRNA regulation. In December, Stark and Kellis reported that both arms
of a single microRNA hairpin can also produce distinct, functional
microRNAs, with distinct targets. Together, these two findings suggest
that a single gene can encode as many as four different functions - one
hairpin from each of the two DNA strands, and then one microRNA from each
of the two arms of each hairpin.



These recent papers are the latest example of the power of using
computational tools to investigate the genomes of multiple species, known
as comparative genomics. The Kellis group has used this approach to
discover protein-coding genes, RNAs, microRNAs, regulatory motifs, and
targets of individual regulators in diverse organisms ranging from yeast
and fruit flies to mouse and human.



"This represents a new phase in genomics-making biological discoveries
sitting not at the lab bench, but at the computer terminal," Kellis says.



Kellis is the Karl Van Tassel Career Development Assistant Professor in
the Department of Electrical Engineering and Computer Science and an
associate member of the Broad Institute. He grew up in Greece and France
and earned his B.S., M.Eng., and Ph.D. from MIT, and he was appointed to
the faculty here in 2004. At 30, he has already earned numerous awards and
accolades, including a place on the list of the 35 top innovators under 35
by Technology Review magazine in 2006.



Kellis' work is supported in part by grants from the National Institues of
Health and the National Science Foundation. Alex Stark is supported by a
Human Frontier Science Program fellowship.

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