Scientists work to break cellular code

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.”