For many years, histones had an unglamorous reputation as the mere packing material of DNA. While appreciated for this role, they were considered utilitarian—not molecules whose study would merit awards. C. David Allis, however, believed histone proteins, which serve as “spools” around which DNA strands are wound, might play a nuanced role in gene expression.
Early in his career, Allis was inspired by the work of Rockefeller’s Vincent Allfrey, who thought histone modification could be a critically important “switch” for gene activation. Allfrey hypothesized that the addition of chemical groups—including acetyl, methyl and phosphoryl—to histones could cause them to expand and contract, permitting access to specific genes. He thought this possibly allowed for both inhibition and reactivation of RNA production at different places along the chromosome, in turn influencing gene expression.
Stirred by this hypothesis, Allis began working with Tetrahymena, an intriguing single-celled organism that has two genomes—one active, one dormant—partitioned in separate nuclei. With its active nuclei teaming with acetylated histones, this “pond water critter” became Allis’s self-declared secret weapon. He used it to search for an enzyme responsible for the chemical changes Allfrey had proposed.
Another scientist, Michael Grunstein of the University of California, Los Angeles, was investigating parallel questions using yeast. By altering its genes, Grunstein succeeded in demonstrating how nucleosomes, sections of DNA coiled around eight histone proteins, play a role in gene regulation. He also showed that a specific histone protein was required in order for yeast to be capable of sexual reproduction. The role of histones in gene regulation was beginning to come to light.
By the mid-90s, Allis’s lab went another step further. With the help of graduate student Jim Brownell, Allis isolated an enzyme from Tetrahymena, called acetyltransferase (HAT), which adds an acetyl chemical group to DNA. This in turn relaxes the tightly bound DNA and makes space for transcription and thus gene expression. They had finally discovered the “on” switch Allfrey hypothesized years earlier.
In recent years, histone science has become a critical component of epigenetics, a growing field that investigates gene regulation that takes place outside of DNA’s preliminary blueprint. Moreover, scientists have revealed druggable targets on histones that increase or deactivate expression of a particular disease-causing gene.
These implications have brought hard-to-treat cancers, including pediatric gliomas, to the forefront of Allis’s research program. He has uncovered how mutations in a particular histone are overly represented in these kinds of tumors. Additionally, Allis and his colleagues have discovered that in leukemia, the protein ENL, a reader of histone acetylation, activates oncogenic gene expression. Mutations to this protein are also implicated in Wilms’ tumor, the most common pediatric kidney cancer. His work, which currently includes clinical investigation, raises the possibility of displacing ENL from chromatin as a potential therapy.
Unlike conventional cancer treatments, these new histone-based approaches aim to correct the conduct of cancer cells by turning off the disease-causing genes. “These drugs are helping cancer patients lead healthier lives,” Allis remarked at the Lasker Award ceremony, during which he and Grunstein were honored. “Basic research and basic histones do matter.”