Shilatifard Lab

Ali Shilatifard, Ph.D.

Investigator

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Guided by "COMPASS," "GPS" and a lifelong love of research, Ali Shilatifard has traveled through a range of scientific specialties, and along the way has gained new insight into the molecular underpinnings of leukemia.

The journey began in Iran, where as a child, Shilatifard could think of nothing more fun than doing experiments. But while other kids his age were peering at pond water through toy microscopes and mixing concoctions with their chemistry sets, Shilatifard was working in a real laboratory alongside his grandfather, a radiologist and physicist with a dual MD-PhD degree.


COMPASS is a multiprotein methyltransferase complex in the Saccharomyces cerevisiae. COMPASS and its mammalian homolog, the MLL complex, modify histone H3 by post-translational methylation and are involved in the regulation of gene expression.

Image: Courtesy of Dr. Shilatifard

"I can still remember the smell of his laboratory," Shilatifard recalls. "I used to help the technicians mix up solutions and distill things. At the age of nine, I was doing infrared spectroscopy and gas chromatography to check the purity of samples."

With that early introduction, it's perhaps not surprising that he took up organic chemistry in college and became proficient at other analytical techniques in graduate school, such as mass spectroscopy and nuclear magnetic resonance spectroscopy. During his postdoctoral work, he learned to purify proteins, but when he started his own laboratory, he decided to go a different direction.

"The very first day, I was sitting at the bench in my lab, thinking about my future in research," Shilatifard says, "I knew there was a finite number of proteins that I could purify, so then what? I also realized I was much more interested in biology and how its misregulation results in human cancer." So as soon as he could arrange it, Shilatifard took two sabbaticals during which he trained himself to be a geneticist.

Today, his lab uses techniques of biochemistry, genetics and cell biology to identify and study factors involved in the regulation of gene expression (the process by which information from a gene is used to make proteins or RNA molecules that are essential to life). The main goals: to identify the molecular-level mix-ups that lead to leukemia with the aim of developing more effective treatments, and to understand how the associated machinery normally functions during development.

One of Shilatifard's first major achievements, during his postdoctoral fellowship, was the identification of the function of a protein called ELL. He went on to show that ELL functions in transcription elongation, a key step in the process that leads to gene expression. Some 15 years ago, Shilatifard and colleagues proposed that the misregulation of the elongation process could lead to certain types of leukemia.

Since then, his lab has made a series of discoveries that substantiated his original hypothesis. A specific subtype of leukemia results when, through a process known as translocation, a gene called MLL becomes fused to any of a number of seemingly unrelated genes. Shilatifard's group found that all of MLL's fusion partners, including ELL, belong to an assemblage of transcription elongation factors they named SEC for Super Elongation Complex.

When MLL fuses with any of these unrelated partners, the whole SEC, much like an entourage, now follows MLL to its normal target genes misregulating their elongation. “This misregulation of gene expression, we think, is what causes leukemia in children," Shilatifard says.

To better understand the workings of MLL, Shilatifard's group turned to the model organism Saccharomyces cerevisiae(yeast), which has an equivalent gene: Set1. They found that Set1 belongs to a complex they named COMPASS (Complex of Proteins Associated with Set1), and they identified COMPASS as the first histone H3K4 methylase. In the cell nucleus, DNA is wound around proteins called histones, and genes are turned off and on by histone methylation and demethylation (addition or removal of one or more methyl groups).

Shilatifard's lab also developed a screening process they call GPS (Global Proteomic analysis in S. cerevisiae) and used it to identify the pathway of molecular players necessary for proper histone methylation and transcriptional regulation by COMPASS. Further, they showed that MLL and its counterparts are found in COMPASS-like complexes in organisms ranging from yeast to humans, an indication of the complex's importance to basic biological processes.

After years in the lab, Shilatifard is still as excited by experiments as he was in boyhood. "Working in the lab, to me, is the greatest hobby of all," he says. "And I have a job doing that! It can't get any better."