Look in any high school biology textbook and you will likely see DNA described as the elegant double-stranded helix. You will learn that long strings of letters form genes, which get switched on to make RNA. Eventually, the RNA is translated into proteins that do work for the cell.
Discovered in Workman's lab in the 1990s, the multi-functional SAGA, short for Spt-Ada-Gcn5-Acetyl transferase, regulates numerous cellular processes through coordination of multiple post-translational histone modifications.
Image: Workman Lab
It seems like a linear, straightforward process. But over the past three decades, Jerry Workman has shown, time and again, that gene regulation is much more complicated.
The human DNA code is some 3 billion letters long; if stretched out in a line, it would span six feet. To squeeze into the tiny nucleus of each cell, every 200 letters or so the DNA wraps around protein balls, called histones, so that it resembles beads on a string. The necklace then gets folded and compressed many times over, ultimately forming finger-like chromosomes.
Workman was one of the first scientists to discover that histone balls are not only important for the exquisite packaging of DNA. They're also crucial players in DNA's transcription into RNA. He has identified several groups of proteins that spur histones to loosen their grip on DNA, leaving it open to enzymes that can read its code and turn on genes.
Figuring out how exactly this unwinding happens has significant implications for understanding natural phenomena—such as cell replication and tissue development—as well as how these processes can go awry. "Gene regulation is very intimately involved in aspects of cancer as well as many other diseases," Workman says.
Workman didn't always have an interest in genetics. Growing up hunting and fishing in a small town in Illinois, he thought he might become a wildlife biologist. That changed in college when he took a class on electron microscopes, which can magnify specimens some 10 million times. "I was preparing the samples, doing the microscopy, doing real exploratory research," he recalls. "That really put me over the top."
The SAGA complex, a transcriptional coactivator, plays an important role in tissue-specific gene expression. A subunit of the complex was tagged with green fluorescent protein in the musculature (top) or nervous system of Drosophila embryos (bottom).
Image: Courtesy of Dr. Vikki Weake, Ph.D., in the Workman Lab.
In 1979, Workman went to the University of Michigan for graduate school, where he used electron microscopy to try to zoom in on tiny pieces of chromatin—the term for the whole DNA/protein package. Most of the experiments he attempted didn't work out, but the technical training was key. "It made me an aficionado in the biochemistry of chromatin," Workman says. "There were very few people who had that skill set at that time."
That served him well during his next gig: a postdoctoral fellowship at Rockefeller University in New York City. Moving to the Big Apple was a tough transition for the Midwesterner. "I had been living in a farm house, where we had to chop up logs for the wood burner," Workman says. "Then I moved to this high-rise Manhattan apartment building. It was quite a shock."
But it was a golden scientific opportunity. He was working in the lab of Robert Roeder, a pillar in the field of gene regulation. Roeder was one of the first scientists to discover transcription factors, proteins that turn on genes in many cell types and many organisms. In Roeder’s lab Workman was able to show that transcription factors and nucleosomes compete for DNA sequences to activate or repress genes.
In his own lab at Pennsylvania State University, Workman identified a slew of protein complexes in yeast that interact with both transcription factors and histones to help turn DNA into RNA. The most famous complex is made of 20 proteins and dubbed SAGA. Workman discovered SAGA, and then figured out many of the molecular pathways in which it plays a part.
For instance, he found that certain transcription factors bind to a particular stretch of DNA, and then recruit SAGA to bind to them as well. SAGA then attaches chemicals, called acetyl groups, to the part of the histone underneath that section of DNA. The acetyl groups make the histone unstable, loosening its bond with DNA.
About 12 years ago, Workman's lab took a slightly new direction after he had a pivotal conversation with his wife, Susan Abmayr, a fruit fly expert whom he had fallen for at the lab bench back at Rockefeller. The two were celebrating their 10th wedding anniversary at a bar in St. Croix when they thought, hey, wouldn’t it be fun to work together again? "That's when we decided to collaborate and look for these complexes in flies," Workman says.
In 2003, the couple moved to Stowers. They carpool every morning to work and use offices in the same hallway. Their working relationship has been extremely fruitful. To give just one example, in 2004 they reported in Science the discovery of a complex in flies, called Tip60, that not only drives DNA transcription, but also DNA repair.
© Stowers Institute for Medical Research