Scientists Work To Break Cellular Code ... Key To Cracking This Code ... Proteins Called Transcription Factors

[Murray Charters <mcharters@xxxxxxxxxxxxxx>]

Public release date: 6-Nov-2003
Contact: Kelli Whitlock or David Cameron
newsroom@xxxxxxxxxx
617-258-5183
Whitehead Institute for Biomedical Research

Scientists work to break cellular code

CAMBRIDGE, Mass. (Nov. 6, 2003) ? Despite the rich knowledge scientists now 
have of the genes that constitute the human
genome, researchers have yet to unravel the precise choreography by which they 
work ? or malfunction ? together in the
cell in response to triggers from the outside world.

"There is a code we need to understand to determine what happens to a cell 
under many different conditions, and
ultimately to make predictions of how an entire genome is regulated," explains 
Julia Zeitlinger, a postdoctoral
associate at Whitehead Institute for Biomedical Research.

Key to cracking this code, she says, is a set of proteins called transcription 
factors, which bind to specific genes to
produce proteins. Akin to computer programs that return different results 
depending on the input data, transcription
factors can carry out multiple functions in the cell in response to distinct 
stimuli.

For example, expose a yeast transcription factor called Ste12 to a certain 
pheromone from a potential mating partner,
and it induces a mating response. But starve the yeast for nutrients, and the 
same transcription factor provokes
filamentation ? the yeast begins to sprout numerous threadlike strands.

Pinpointing the mechanism that makes transcription factors such as Ste12 
respond differently under different
environmental inputs could enable scientists to better predict cellular 
behavior and disease pathology.

In a study published earlier this year in the journal Cell, Zeitlinger and 
colleagues at Whitehead discovered that when
a multipurpose transcription factor is exposed to a particular environmental 
condition, it directly orchestrates a
global change throughout the genome in binding sites involved in the cellular 
behavior induced by that condition.

The team monitored all binding sites of the transcription factor Ste12 in yeast 
while exposing the genome to the
pheromone that induces mating and to butanol, an alcohol that mimics the 
conditions that promote filamentation. They
used a technique called genome-wide location analysis, a process pioneered by 
Whitehead Member Richard Young that uses
DNA microarrays to enable rapid analysis of protein interaction with the DNA of 
an entire genome.

"When we profiled the binding sites of Ste12 under the two developmental 
conditions, we found that Ste12 indeed
undergoes the predicted global switch in binding," recalls Zeitlinger, who 
works in Young's lab and collaborates with
scientists at MIT's The Broad Institute. The researchers found that this 
transcription factor, rather than activating a
chain reaction of other transcription factors in the cellular network, directly 
determines which genes are activated
under each condition.

Zeitlinger plans to investigate if this mechanism occurs generally in yeast and 
higher organisms, work that ultimately
could help physicians better understand, diagnose and disrupt certain diseases 
at the cellular level.

"Ste12 is able to undergo the switch in binding because of its cooperative 
interaction with another transcription
factor, Tec1," Zeitlinger says. "My hypothesis is that there are different 
types of cooperative interactions between
transcription factors. By defining them and understanding how they work, I hope 
to construct a grammar to the
regulatory code. This will help to make predictions of cellular behavior based 
on DNA sequence."

###

Written by Mark Dwortzan, a freelance science writer in Cambridge, Mass.

The research was supported by the Human Frontier Science Program.

Full citation for print version
® Cell, Vol 113, 395-404, 2 May 2003
"Program-Specific Distribution of a Transcription Factor Dependent on Partner 
Transcription Factor and MAPK Signaling"
Authors: Julia Zeitlinger,* Itamar Simon, (1), Christopher T. Harbison, Nancy 
M. Hannett, Thomas L. Volkert, Gerald R.
Fink, and Richard A. Young*

*Whitehead Institute for Biomedical Research Nine Cambridge Center
Cambridge, Massachusetts 02142
(1) Present address: Hebrew University Medical School, Department of Molecular 
Biology, Hadassah Ein Carem, Jerusalem
91120, Israel.

SOURCE: EurekAlert


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