A deeper look at gene control
CAMBRIDGE, Mass. (August 17, 2006) — Don’t
be fooled by those neat and orderly textbook illustrations
of the inside of a cell. Cellular activity resembles
Grand Central Station at rush hour far more than it
resembles a game of croquet. Countless proteins and
organelles are squeezed together, pitching signals back
and forth and back again, carrying out tens of thousands
of simultaneous functions.
The control center for all this hustle and bustle is
the genome, which stores the operating instructions
and responds to extracellular events. It receives its
intelligence about the outside world via signal transduction
pathways—designated routes by which long lines
of proteins pass on a piece of chemical information
from the cell surface all the way into the nucleus,
bucket-brigade style.
While researchers have gotten pretty good at understanding
these pathways, they get stumped at the last few steps,
at the precise moment that this pathway concludes in
the expression of a particular gene. This is because
while evolution has conserved signal transduction pathways
throughout many species, it has not conserved the specific
gene that the pathway targets. If pathway A in the fruit
fly leads to gene B, that same pathway in the mouse
may instead lead to gene D. This knowledge gap poses
a significant problem, because understanding exactly
how specific pathways activate particular genes is essential
for drug development.
In a recent paper published in Science, scientists
in the lab of Whitehead Member Richard
Young, led by postdocs Dmitry Pokholok and Julia
Zeitlinger, report that a well-known class of proteins
called kinases may fill in the dotted lines that connect
signal transduction pathways to the genes they regulate.
| “Most molecules associated with gene regulation
bind to regions just outside the gene," says
Whitehead postdoc Julia Zeitlinger. "Here,
however, the kinases were located directly on the
protein-coding regions of the genes. We never expected
that.” |
Kinases are enzymes, proteins whose main function is
to catalyze a reaction in other proteins. In particular,
kinases target transcription factors, proteins that
switch genes on and off. Researchers know that most
(though not all) kinases reside in the cell’s
nucleus. But they have never paid much attention to
the kinases’ exact locations, reasoning that if
a kinase is technically able to activate a transcription
factor from any place in the cell, its precise location
is probably not important.
Using microarrays to analyze the whole genomes of yeast
cells, Pokholok and Zeitlinger decided to track down
the location of kinases that reside in the nucleus.
The results were surprising.
“Many kinases we studied were physically associated
with the genome and some of them were located right
on the gene itself,” says Zeitlinger. “This
surprised us because most molecules associated with
gene regulation bind to regions just outside the gene.
Here, however, the kinases were located directly on
the protein-coding regions of the genes. We never expected
that.”
This surprise was pleasant because, unlike other molecules
involved in gene expression, kinases are relatively
easy to connect back to the signal transduction pathways.
“This might just turn out to be invaluable for
understanding how these cellular pathways relate to
gene expression,” says Zeitlinger.
The next step, adds Pokholok, is to confirm these findings
in higher organisms.
|
