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Deciphering an elephant
June 2008--As a mega-discipline that requires—and attracts—broad, outside-their-own-discipline thinkers, epigenetics is like an elephant, says Andy Feinberg, director of the IBBS Center for Epigenetics.
“Unfortunately, research in the basic sciences can resemble the blind men and the elephant,” says Feinberg, referring to the fable in which one man touches a pachyderm’s stout leg and assumes the animal is a pillar; another, the muscular trunk, and thinks snake—and so on. “That’s why we are very excited Sean Taverna has joined this Center, the vision for which is for researchers to ask questions and share ideas about basic research from all different angles, as well as to collaborate on experiments and grant-writing.”
Taverna, an assistant professor of pharmacology and molecular sciences, has research interests that include histone and chromatin modifications, epigenetics and gene function, identification of histone binding proteins, and RNA-mediated gene silencing.
Over the past decade, researchers at Hopkins and other institutions have discovered that epigenetic modifications—chemical modifications of DNA and the proteins associated with DNA that don’t affect the DNA sequence itself and are remembered during cell division—can have a profound impact on gene transcription and play a role in processes ranging from cell differentiation to the development of cancerous cells.
Epigenetics researchers are “all just tinkerers at heart,” says Taverna, who, while a postdoc at the Rockefeller University helped discover that small interfering RNAs, or siRNAs, are important for guiding gene silencing machinery. Disrupting siRNA manufacture, says Taverna, removes gene silencing and prevents heterochromatin formation.
One of his many goals here is to fill in some blanks in the gene silencing pathway: “The siRNA pathway is of critical importance since we know some of its components are up-regulated in certain types of cancer,” Taverna says. “Presumably, this means that tumor-suppressor genes that normally prevent cells from growing out of control are being silenced—the problem is that we don’t know what it is that is actually shutting these genes down.”
His main area of investigation is the link between gene transcription and specific modifications of histones—he and others teased out that the location of methyl groups on histones helps determine which proteins will interact with chromatin, and these proteins dictate whether or not the gene is transcribed. “The problem,” says Taverna, “is that we still don’t know exactly how histone methylation is targeted to specific sites of the genome.”
Methylation on an N-terminal lysine binds PHD (plant homeodomain)-containing proteins. And PHD-containing complexes that also contain histone acetyltransferase (HAT) can acetylate histones and activate gene transcription. On the other hand, histone methylation at other sites can attract binding of chromodomain proteins, which are associated with heterochromatin and gene silencing.
“When I started in this field, this paradigm was just becoming appreciated and it remains very exciting,” says Taverna.
A top priority now, he says, is figuring out how methyl marks and the proteins that bind them find their way to the right genes. “Somehow, these modifiers know where to go—it’s like there is some sort of zip code that directs them to the right genomic address. There are 80 to 100 different types of post-translational histone modifications that probably play a role in giving directions. We’re not sure how this happens yet, but it’s a fascinating puzzle.”
To study how histone marks contribute to an “epigenetic/histone code” that may dictate chromatin-templated functions like transcriptional activation and gene silencing, as well as how these on/off states are inherited and propagated, Taverna employs biochemistry and cell biology in a variety of model organisms ranging from mammals to yeast and ciliates.
“I’m excited about working with my colleagues in the Center for Epigenetics because, by pooling our resources, we have a real opportunity to figure out how all this happens,” Taverna says. “The more we understand this, the better we can apply this knowledge to clinical applications and target drugs to enhance or prevent the transcription of certain genes.”
Feinberg couldn’t agree more. “We’re all stronger for working together. By doing this, we have the possibility of seeing the whole elephant."
Sean Taverna on potential cancer treatments