Cells deploy an arsenal of enzymes to chemically modify DNA and its protein packaging. These so-called epigenetic modifications regulate the expression of genes, tuning the function of individual cells.
Neuroscientists have found that, in neurons, this enzymatic arsenal plays a significant role in learning and memory. And data suggest that dysfunction of epigenetic machinery is linked to neurological and psychiatric disorders, such as Alzheimer’s disease, schizophrenia, and depression.
Now a team of researchers at Massachusetts General Hospital led by Jacob M. Hooker reports a way to study one kind of epigenetic enzyme in living people’s brains using positron emission tomography, or PET (Sci. Transl. Med. 2016, DOI: 10.1126/scitranslmed.aaf7551).
“It’s a powerful new tool,” says Javier González-Maeso of Virginia Commonwealth University, who was not involved in the work.
The PET method maps the pattern of expression of epigenetic enzymes called histone deacetylases (HDACs), which pull acetyl groups off of proteins that package DNA in cells. “All of the studies on these enzymes so far have been in tissue culture or in animal models—in mice and rats,” González-Maeso says. “So this is the first study showing the expression of these epigenetic targets in humans.”
To measure the density of HDACs in the brain using PET, Hooker and his colleagues developed a radiolabeled molecule that can bind these enzymes. They tested hundreds of analogs of known HDAC inhibitors to pinpoint a molecule that could bind a specific class of HDACs, pass through the blood-brain barrier, and accurately quantify enzyme levels in the brains of rodents and nonhuman primates. The result was the molecule [11C]Martinostat.
In the new study, the researchers used the molecule to image the brains of eight healthy volunteers. They found that the pattern of HDAC expression was similar among the subjects.
The team also performed a preliminary study in cell culture to better understand the genes regulated by the HDACs that [11C]Martinostat inhibits. By identifying the genes controlled by these HDACs, Hooker says researchers studying patients with certain neurological diseases could use density maps produced by [11C] Martinostat to determine the genes whose regulation is disrupted in that particular disorder.
Hooker’s lab has already started imaging patients with schizophrenia, Huntington’s, and Alzheimer’s disease.
Besides determining how HDAC expression differs in disease states in the brain, González-Maeso also thinks the technique could monitor how the enzyme levels change over the course of a patient’s treatment to assess the efficacy of the therapy and to better understand its mechanism.