Danesh Moazed's father was not a scientist, but he passed on to his son a belief that experiments were the only way to truly understand nature. "My father's last words to me as I left Iran were 'I hope you are going to be a true searcher,' meaning a seeker of truth," Moazed says.
And that's just what he has become. A Harvard Medical School cell biology professor and biochemist, Moazed is known by his colleagues for an uncanny intuition that helps him home in on just the right experiment to answer core biological questions.
Moazed did his graduate research training with Harry Noller at the University of California, Santa Cruz, studying the role of ribosomal RNAs in protein synthesis. After finishing graduate school, Moazed recalls, "my interests were inclined toward understanding how development works, how a single egg can produce a whole adult organism." While doing postdoctoral research at the University of California, San Francisco, he used fruit flies and then yeast to focus that interest on understanding how genes are regulated over the long term.
All cells in an organism contain the same set of genes. In fruit flies, there are about 13,000; humans have more than 20,000. But each cell turns on only the small subset of genes that it needs to carry out specialized functions. Liver cells have no use for the genes that help transmit a nerve impulse, for example, so they remain shut off for the life of the cell. What's more, as these specialized cells divide, daughter cells retain the gene activity pattern of their parents. "There are many different kinds of cells in the human body." Moazed says. "But how do they maintain their stable identities?"
Epigenetic control mechanisms are modifications that alter gene activity across generations without changing DNA, the genetic code. Cells use a variety of strategies to achieve this control. Moazed focuses on understanding how DNA packaging—into a structure called chromatin—helps keep genes in their appropriate on or off state.
It is unclear how genes maintain a memory of their developmental history and remain shut off through numerous cell divisions. But genes that remain stably shut off typically lie in regions of chromosomes that are packaged into an altered form of chromatin that prevents their expression. This altered chromatin appears to be inherited during cell division. Heterochromatin, which literally means "different chromatin," is one type of altered chromatin.
"Genes that are packaged in this way are stably turned off, and the off state is remembered over long periods and many cell divisions," Moazed explains. Scientists have made considerable progress in understanding how packaging into heterochromatin turns genes off, but how that off state is inherited during cell division remains unclear.
Working with yeast—a relatively simple, single-celled organism—Moazed has focused on understanding the machinery that packages DNA into heterochromatin. Results from his lab and others challenged the idea that this protective packaging depends entirely on cellular proteins. Instead, small RNA molecules play an important role in maintaining the "off" state. "With this simple system we're learning about entirely new ways that genes are regulated," he explains.
RNA is best known as a messenger that relays genetic information from DNA to the cellular machinery that builds proteins. But in the past two decades, scientists have become increasingly aware that it plays a pervasive role in regulating genes as well. In particular, small RNA molecules of only about 20 nucleotides work through an RNA silencing pathway known as RNA interference to regulate nearly every aspect of gene expression. Moazed's research has identified the machinery that uses small RNAs to guide the proteins that build the tightly bound heterochromatin over the correct stretch of DNA. Through biochemical experiments, his team has worked out many details of how this occurs. Interestingly, the process shares many of the same tools cells use for RNA interference.
Moazed suspects that more complex organisms will share the gene-silencing mechanisms he studies in yeast, and, as an HHMI investigator, he plans to find out. He will begin studying whether small RNAs target chromosomes in mammalian cells, and how the system might be involved in transforming stem cells into different cell types with specialized functions.