In the Japanese art of paper folding, a series of folds can make the same sheet of paper into a ballerina or baby elephant. But try unfolding the baby elephant and making it into a ballerina. It's like trying to make a neuron from a kidney cell. Epigenetics, it turns out, isn't much different from this old Japanese art: Each fold, or epigenetic crease, both limits and permits further potential folds in a way that mirrors how epigenetic changes seal a cell's fate.
The changes occur on the tails of histones, the globular proteins around which DNA winds itself to make chromatin, the stuff of chromosomes. When the strings of amino acids that make up the tails undergo epigenetic modifications - chemical alterations such as methylation or acetylation - chromatin's structure changes in order to either seal off DNA or make it available for transcription. Like each fold of the paper, each modification ultimately shapes chromatin's structure.
In a genome-wide study led by George A.M. Cross, head of the Laboratory of Molecular Parasitology, and T. Nicolai Siegel, a graduate student in the lab, scientists at Rockefeller University have mapped epigenetic changes that are likely to play a role in initiating the transcription of genes in Trypanosoma brucei, the deadly single-celled parasite responsible for African sleeping sickness. The advance marks the first time scientists have been able to develop the tools to map these changes across the entire genome of the evolutionarily ancient parasite.
"Histones in trypanosomes are extraordinarily divergent from histones in other organisms, so we couldn't use the same commercially available antibodies we use for mammals and yeast to isolate them and study their modifications," says Cross. "If we were interested in histone modifications, we couldn't reliably predict which amino acids in the histone tails would be modified and had a role in transcription. We now have the means to do that."
Two years ago, Cross and his colleagues were the first to identify histone modifications that exist in T. brucei, focusing on modifications that occur on H4, one of the four pairs of core histones. Building off that research, Siegel was able to create an antibody specific to the modified histone, whose 10th amino acid was acetylated. When the antibody was exposed to the trypanosome genome, it attached to the modified histones, allowing Siegel to extract them - along with the DNA coiled around them - from the parasite's nucleus.
"What I had was all these DNA fragments, which I could then map back to the genome and see every location where this modification occurred," says Siegel.