February 2005--The study of epigenetics—heritable changes in gene function due to something other than altered DNA sequence—is not a new science, but it has become newly significant. Before 1990, the idea that diseases like cancer could be driven by epigenetic changes or that epigenetic “imprinting” of DNA helps drive normal development was controversial. However, a series of discoveries, some of them at Hopkins , has radically altered that view.
“There's been a revolution,” says geneticist Andy Feinberg, director of Hopkins' NIH-funded Center for the Epigenetics of Common Human Disease. “Until the 1990s or so, epigenetics referred mostly to the study of strange phenomena in species other than humans. It was weird science.”
Then investigators rediscovered the importance of chromatin and methylation in helping turn genes on and off.
Chromatin is the protein-laced DNA packaging of eukaryotic cells. Much of a cell's DNA is found in chromatin, yet for a time people believed that it “must be inert stuff that gets pushed out of the way as DNA is transcribed to make RNA,” says structural biologist Cynthia Wolberger.
However, the discovery, in eukaryotic cells, of specific enzymes that bind to proteins in chromatin—and the related understanding that the enzymes were modifying those proteins—enabled people to understand that “packaging” material is critically important. It's not just a bystander in gene regulation.
Methylation—the addition of a methyl group to DNA or proteins—captured the attention of Hopkins cancer researcher Steve Baylin in the mid-1980s. Baylin and his co-investigators noticed excessive methylation in a cancer cell model, in a gene promoter region that was normally free of methyl groups.
“That raised the possibility that tumor suppressor genes, genes which ought to be turned on, might be inactivated by methylation,” Baylin says.
This was a revolutionary idea, as dogma dictated that genetic mutations—changes in DNA sequencing—caused most cancer.
“The idea that the DNA base sequence would stay the same in a gene's promoter region while DNA methylation could change, and shut off the gene—that met with tremendous resistance,” he says.
Nonetheless, discoveries like these helped pave the way for an explosion of basic science research that has increasingly illuminated how a gain or loss of epigenetic “marks” like methyl groups affects not only disease development, but also phenotype. Some of that work is being carried out here at Hopkins , in Cynthia Wolberger's lab.
Wolberger’s focus is the enzyme Sir2, which plays an important role in regulating the lifespan of yeast, worms and flies. Sir2 achieves these effects by binding to and modifying proteins in chromatin, thereby instigating transcriptional silencing (preventing DNA from being read to make RNA). The human version of Sir2 has been implicated in a number of disease processes, including ones in diabetes and inflammation, as well as in normal aging.
Wolberger says, “We have some ideas of actually modulating its activity, which might lead to a drug one day.”
A basic scientist to her bones, Wolberger doesn't intend to carry that research to the clinic herself.
“We've learned so much in the past couple of decades,” she says, “and it's a really exciting time for applying that research to human disease. But we won't be able to continue translational research without first fostering the fundamental discoveries that drive that whole machine.”
Cancer researcher Baylin sees tremendous therapeutic potential in the epigenetics research coming out of Hopkins labs.
“There are now very sensitive PCR techniques to detect methylation change,” he says, adding that they are “very promising for early detection of cancer.”
These early detection assays use methylation changes in DNA-rich sputum or serum as a biomarker for diseases like prostate cancer. The assays developed and the data accumulated so far is promising, Baylin says, adding that epigenetics research encourages researchers to “talk across disciplines. It makes disease-related work much more seamless with basic science.”
Feinberg, a strong advocate for an integrated epigenetic and genetic approach to studying human disease, agrees that “there's wonderful communication between both sides of the street—the translational and clinical sides, and the basic sciences.”
“There's really good reason to believe that epigenetic changes are at the heart of what distinguishes a stem cell from a somatic cell,” he says. “So, being able to apply some existing and some new epigenetic tools to the issues of stem cell biology would be really powerful.”
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