Zeitlinger Lab

On the stage of science, a researcher plays many roles: experimenter, author, laboratory director, mentor. If Julia Zeitlinger seems particularly adept at segueing from one role to another, perhaps it's because of her early training in theater.

"I was seriously considering becoming an actress," she recalls. "I loved being on stage, bonding with the cast and crew, developing the play, getting into the role." But she also was drawn to math and science, and her desire to find life work that might benefit other people led her to study biology, with an eye toward medical research.

"I knew that I would be good at science, but at first I wasn't sure I had the same passion for it that I had for acting," Zeitlinger admits. Over time, though, she found that being at the forefront of science was just as thrilling as being front and center on stage.

The goal of Zeitlinger's research is uncovering the rules that govern gene regulation -- the all-important process by which a cell determines which genes to turn on and off and when. She then hopes to use that knowledge to predict the fate of a given cell.

Every cell in the human body holds a complete copy of that individual's DNA, but not all of the tens of thousands of genes contained therein are expressed in any given cell; decisions must be made. For example, a cell destined to become a neuron turns on genes that take it down that path, but leaves genes turned off that would make it a bone cell or a skin cell. What's more, cells have different needs and functions at different times in their lives, requiring particular genes to be activated or repressed.

"Rather than focusing on single genes and addressing how each gene is regulated, we're trying to understand the general principles," Zeitlinger says. To uncover those principles, she works with the model organism Drosophila (the fruit fly), but she believes her findings ultimately will be applicable to humans and will further understanding of not only how genes are normally regulated, but also how regulatory mechanisms are hijacked in disease.

"If we understand the general framework, we'll have the tools to decode what's really going on during disease and to understand how individuals differ in what makes them susceptible to disease," Zeitlinger says. "For example, in the future we could look at a cancer cell and determine from its DNA sequence not only what has gone wrong, but also the history and fate of the cell – where it came from, what it's going to do in the future and whether it will respond to particular treatments."

Zeitlinger's lab is exploring two main modes of gene regulation: regulation dictated by DNA sequence, and regulation based on chromatin state. (Chromatin is DNA combined with the proteins that package DNA in the cell nucleus. The structure, or state, of chromatin is always changing, rendering particular regions of DNA more or less accessible).

To understand how DNA sequence is linked to regulatory activity, Zeitlinger's group is studying the evolution, composition and developmental function of cis-regulatory elements, sections of DNA that regulate the expression of nearby genes. In one recent publication, Zeitlinger and coauthors analyzed the evolution of DNA sequences to which a protein called Twist binds. Twist is a transcription factor, a type of protein that binds to specific DNA sequences to initiate transcription (the first step in gene expression). The researchers found that the sequences to which Twist binds increasingly changed over the course of evolution in Drosophila, but that Twist could still bind to most of them. This suggests that, as DNA sequences mutate over time, natural selection makes sure that important sequences, such as those to which Twist binds during embryonic development, remain functional.

In other work, the Zeitlinger lab is "reading" chromatin to discern the developmental history of cells, with the hope that the information also can predict the cell's future course.

Zeitlinger's research already has led to one such molecular crystal ball. As a postdoctoral fellow in the lab of Richard Young at the Whitehead Institute for Biomedical Research at Massachusetts Institute of Technology, Zeitlinger made a surprising discovery about RNA polymerase, a critical enzyme in transcription. Previously, it was thought that once RNA polymerase is recruited to the work site, transcription proceeds without a hitch. But Zeitlinger discovered that for many important developmental genes, RNA polymerase starts the transcription process, but then pauses, as if waiting for a signal to proceed.

"If paused polymerase is present, the gene is more likely to be activated in the future," Zeitlinger says. Her lab now is investigating how well paused polymerase can predict gene expression at any stage of development.

"The vision," Zeitlinger says, "is that you can one day apply these predictive tools to disease cells, that you can look inside and see what the cell has been doing in the past and what its potential is."

If that, indeed, comes to pass, Zeitlinger and her cast of coworkers surely will deserve to take a bow.